REVIEW ARTICLE

CARDIAC TRANSMEMBRANE ION CHANNELS

AND ACTION POTENTIALS: CELLULAR
PHYSIOLOGY AND ARRHYTHMOGENIC
BEHAVIOR
Remodeling Genetic mutations,
AUTHORS
Channel/protein expression

, Jakub Tomek, Norbert Nagy,
(disease, chronic drug) polymorphisms
András Varro
Acute drug effects
Acute diseases
Transmembrane ion channel/pump function Hormones Gender
Virág, Elisa Passini, Blanca Rodriguez,
Lászlo
(e.g. ischemia)
Transmembrane cellular voltage change
X+
Amp
István Baczko

X+
Single cell action potential X+ +
Plasma electrolyte X+ X
alterations
Tissue action potential + impulse conduction Amp
Single cell action potential + electrotonic interaction Ce

Whole heart summated electrical signal

CORRESPONDENCE
Electrocardiogram – clinical diagnostic tool
varro.andras@med.u-szeged.hu
TdP
Arrhythmia
AF Substrate Trigger
VF

Impulse Repolarization/ERP Triggered activity

Enhanced normal
automaticity
KEY WORDS
conduction heterogeneity
DAD EAD SAN Purkinje fiber
action potential; arrhythmia; heart; ion channels;
remodeling

Pathological settings

Plasma electrolyte Myocardial Heart HCM/ Diabetes Inherited/genetic Drugs/Dietary ingredients

imbalance ischemia failure Athletes heart mellitus abnormalities

CLINICAL HIGHLIGHTS
1. Cardiac arrhythmias are major causes of mortality. They most often arise from pathological changes in the electro-
physiological properties of myocardial cells. First, this review summarizes the physiology of cardiac action poten-
tials, their regional and species differences, the underlying transmembrane ionic currents, and transporters, with
special focus on their human relevance.
2. Progress in computer modeling and vast quantities of experimental data made computerized replication of the action
potential, impulse conduction, and simulation of cardiac electrophysiology possible. Current computer models offer
improved observability and controllability via utilization of different modeling scales and can assist future individualized
anti-arrhythmic therapy as well as drug electrophysiological safety assessment.
3. A number of diseases evoke changes in the configuration of the action potential caused by altered function and/or den-
sities of transmembrane ion channels and transporters, collectively termed electrical remodeling. Initially, these altera-
tions are often compensatory; however, remodeling significantly contributes to increased arrhythmia susceptibility by
impairing impulse generation, conduction, and myocardial refractoriness in these clinical settings. Electrical remodeling
in atrial fibrillation, heart failure, hypertrophic cardiomyopathy, myocardial infarction, and advanced age are discussed.
Better understanding of the cellular basis of cardiac electrophysiology, electrical remodeling, and mechanisms of
arrhythmias has important implications for future clinical therapeutic strategies.

VARRÓ ET AL., 2021, Physiol Rev 101: 1083–1176

October 29, 2020; Copyright © 2021 The Authors. Licensed under Creative Commons Attribution CC-Y 4.0. Published by the American
Physiological Society
https://doi.org/10.1152/physrev.00024.2019
Downloaded from journals.physiology.org/journal/physrev (187.190.175.238) on November 6, 2023.
 Physiol Rev 101: 1083–1176, 2021
First published October 29, 2020; doi:10.1152/physrev.00024.2019

REVIEW ARTICLE

CARDIAC TRANSMEMBRANE ION CHANNELS

AND ACTION POTENTIALS: CELLULAR
PHYSIOLOGY AND ARRHYTHMOGENIC
BEHAVIOR

,1,2 Jakub Tomek,3 Norbert Nagy,1,2 Lászlo
András Varro
Virág,1 Elisa Passini,3 Blanca Rodriguez3, and István Baczko

1
1
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary; 2MTA-SZTE
Cardiovascular Pharmacology Research Group, Hungarian Academy of Sciences, Szeged, Hungary; and 3Department of Computer
Science, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom

Abstract
Cardiac arrhythmias are among the leading causes of mortality. They often arise from alterations in the electro-
physiological properties of cardiac cells and their underlying ionic mechanisms. It is therefore critical to further
unravel the pathophysiology of the ionic basis of human cardiac electrophysiology in health and disease. In the
first part of this review, current knowledge on the differences in ion channel expression and properties of the
ionic processes that determine the morphology and properties of cardiac action potentials and calcium dynam-
ics from cardiomyocytes in different regions of the heart are described. Then the cellular mechanisms promoting
arrhythmias in congenital or acquired conditions of ion channel function (electrical remodeling) are discussed.
The focus is on human-relevant findings obtained with clinical, experimental, and computational studies, given
that interspecies differences make the extrapolation from animal experiments to human clinical settings difficult.
Deepening the understanding of the diverse pathophysiology of human cellular electrophysiology will help in
developing novel and effective antiarrhythmic strategies for specific subpopulations and disease conditions.
action potential; arrhythmia; heart; ion channels; remodeling

1. INTRODUCTION 1083 CLINICAL HIGHLIGHTS

2. CARDIAC ACTION POTENTIAL 1086
1. Cardiac arrhythmias are major causes of mortality. They most
3. TRANSMEMBRANE ION CHANNELS AND... 1087 often arise from pathological changes in the electrophysiolog-
4. TISSUE-SPECIFIC ACTION POTENTIALS 1107 ical properties of myocardial cells. First, this review summa-
5. COMPUTER SIMULATIONS OF ACTION... 1117 rizes the physiology of cardiac action potentials, their regional
6. CELLULAR ARRHYTHMIA MECHANISMS 1120 and species differences, the underlying transmembrane ionic
7. ION CHANNEL AND ACTION POTENTIAL... 1126 currents, and transporters, with special focus on their human
relevance.
8. INHERITED CONDITIONS ASSOCIATED... 1132
2. Progress in computer modeling and vast quantities of experimen-
9. OTHER FACTORS INFLUENCING... 1134 tal data made computerized replication of the action potential,
10. CONCLUSIONS 1136 impulse conduction, and simulation of cardiac electrophysiology
possible. Current computer models offer improved observability
and controllability via utilization of different modeling scales and
can assist future individualized anti-arrhythmic therapy as well as
drug electrophysiological safety assessment.
1. INTRODUCTION 3. A number of diseases evoke changes in the configuration of the
action potential caused by altered function and/or densities of
transmembrane ion channels and transporters, collectively
The heart is a mechanical pump with the vital role of termed electrical remodeling. Initially, these alterations are often
supplying blood to other organs. In humans, it contracts compensatory; however, remodeling significantly contributes to
and relaxes in a regular fashion 60 times per minute. If increased arrhythmia susceptibility by impairing impulse genera-
the regular heartbeat is interrupted for more than a cou- tion, conduction, and myocardial refractoriness in these clinical
settings. Electrical remodeling in atrial fibrillation, heart failure,
ple of minutes, the lack of oxygen supply causes irre- hypertrophic cardiomyopathy, myocardial infarction, and
versible damage to vital organs, including the heart advanced age are discussed. Better understanding of the cellu-
itself, potentially causing sudden cardiac death (SCD). lar basis of cardiac electrophysiology, electrical remodeling, and
mechanisms of arrhythmias has important implications for future
Cardiac contractions, the most important function of the
clinical therapeutic strategies.
heart, are initiated by a bioelectrical signal, the action

0031-9333/21 Copyright © 2021 The Authors. Licensed under Creative Commons Attribution CC-BY 4.0. 1083
Published by the American Physiological Society.
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 VARRÓ ET AL.
potential (AP) (1), via a process called excitation-contrac-
tion coupling (2). The action potential originates in the
sinus node cells, propagates through the whole heart
via an active electrophysiological process called impulse
conduction, and can be measured as the electrical
potential difference between the intra- and extracellular
space. The stimulus spreads through both atria, causing
their contraction. The next stage of propagation is the
atrioventricular (AV) node, which passes the signal to
the ventricles with a slight delay to provide enough time
for the atria to contract. From the AV node, the bundle
of His conducts the stimulus along the septal wall
to the subendocardial Purkinje fibers, which then stimu-
late the ventricles, allowing their synchronized contrac-
tion. The action potential is determined by the opening
and closing of various complex transmembrane pro-
teins, which consist of ion channels and transporters,
i.e., pumps or exchangers (3–5). Disturbances of action
potential generation and/or conduction can lead to
changes in the regular heart rhythm called arrhythmias
(6, 7). These disturbances can impair contraction to such
a degree that thromboembolic stroke of atrial origin or
sudden cardiac death may eventually occur. Therefore,
understanding the function and regulation of transmem-
brane ion channels and transporters, as well as their
impact on the cardiac action potential, is essential to
understand arrhythmia mechanisms and treat life-threat-
ening cardiac arrhythmias. Arrhythmias are usually diag-
nosed based on the analysis of electrocardiogram (ECG)
recordings, which represent the electrical activity of the
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heart as measured on the body surface. The ECG is
determined by many variables, including the function of
transmembrane ion channels and transporters in the dif-
ferent heart cells and the consequent changes in the
membrane potential (FIGURE 1).
The P wave corresponds to the activation (depolari-
zation) and early repolarization of the atrial cells. The
QRS complex reflects the time course of the depolari-
zation of the ventricles caused mainly by the activation
of the fast sodium channels. The PQ segment mainly
indicates the impulse conduction from the atria to the
ventricles. The PQ segment also contains the HQ inter-
val, which reflects fast propagation due to the function
of the fast sodium current (INa). In addition, cell-to-cell
coupling is low in the AV node (8), which makes
impulse propagation through the AV node relatively
unsafe. The isoelectric ST segment reflects the plateau
phase of the ventricular action potentials. In this phase,
membrane potential hardly changes at the cellular
level because of the fine balance of opening/closing of
different ion channels. The configuration of the T wave
shows the repolarization time course of the ventricles,
and it reflects the balance between the slowly activat-
ing repolarizing potassium and chloride currents and
the depolarizing steady-state, so-called “window” so-
dium (9) and “window” calcium (10) and the slowly
decaying, often called “late,” sodium (INaLate) and
slowly inactivating calcium currents (11–15). Analysis of
the PP intervals yields important information regarding
heart rate and its regularity.
FIGURE 1. Regional differences in cardiac
action potential configurations. Schematic cross
section of the heart depicting the corresponding
action potential configuration from different
regions of the heart indicated by arrows.
Color-coded sections on the action potentials
refer to the corresponding sections on the
schematic electrocardiogram (ECG). AVN,
atrioventricular node; Endo, endocardial; Epi,
epicardial; Mid, midmyocardial; SAN, sinoa-
trial node.
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS

FIGURE 2. A, top: an area of branching cardiac tissue, providing separate paths for impulse propagation from proximal (1) to distal (2–4) directions. The
separate paths for impulse conduction can be variable, as branching Purkinje fiber-ventricular junctions, ventricular muscle segments with nonconducting
fibrosis, scar, or infarcted tissue in the core. If the tissues in these paths are healthy, the impulse conduction is fast and, because of the relatively long effec-
tive refractory period (ERP) in cardiac cells, impulses would collide at site 4 and would propagate only into the distal directions. Bottom: an area of depolar-
ized myocardium at site 3, due to asymmetric severe local myocardial damage, imposing conduction block from the anterograde direction. However, in
the case that the impulse travels from site 4 in the retrograde direction, it can propagate back very slowly into this damaged area, and if its propagation is
slow enough to outlast the ERP in front the impulse can reexcite the proximal tissue. Then, this impulse would propagate toward both sites 1 and 2, estab-
lishing a circus movement and reentry arrhythmia. B: example of a classic mechanism by which a premature ventricular complex (PVC) initiates reentry in
the fibrotic border zone of an infarct, due to slow conduction and dispersion of refractoriness. Top: a PVC occurring 250 ms after the previous beat arrives
too early to propagate through the upper myocyte strand with a long ERP of 275 ms, but it propagates successfully (red arrows) through the lower strand
with a shorter ERP of 225 ms (entry site). The impulse propagates slowly (slow CV), eventually reaching the upper strand from the opposite direction.
Bottom: if the total conduction time is >275 ms, the interface of the upper strand with normal tissue (exit site) has recovered excitability, and the impulse
can then propagate through the region of prior conduction block, thus initiating reentry. Dispersion of refractoriness is caused by electrical remodeling.
The slow propagation is due to zig-zag conduction through the myocyte strands as well as gap junction remodeling. (Reproduced from Ref. 17 with permis-
sion.) C: schematic illustration of functional reentry mechanism without a well-defined anatomical obstacle. The arrhythmia substrate is represented by arti-
ficially enhanced action potential duration differences. In normal circumstances, impulses originating from the sinus node (black arrows) use physiological
pathways to propagate through atrial and ventricular tissue and the conduction system. An early ectopic impulse (trigger, red arrow) can only propagate
via pathways where the tissue is not depolarized, and consequently its refractoriness is over, whereas the conduction is blocked in directions where the
tissue is not fully repolarized and cells are still in the refractory state. Thus the abnormal impulse can travel in a zig-zag direction through reentry paths cre-
ated by heterogeneous repolarization and conduction. The dispersion of repolarization creates a time window called the vulnerable period, where extra
stimuli could elicit the reentry arrhythmia. However, outside this window extra stimuli would only cause a single or multiple relatively harmless extrasys-
toles. CV, conduction velocity; ES, extrasystole; SR, sinus rhythm. Reproduced from Ref. 18 with permission.

Cardiac arrhythmia mechanisms are still the sub-
ject of intensive research. Because of the large vari-
ability in appearances, types (e.g., bradycardia and
different types of tachycardia), locations (supraven-
tricular or ventricular), and underlying diseases, it is
widely accepted that there is not a single mechanism
to explain how arrhythmias originate. Therefore,
patients are often treated with little knowledge
regarding the mechanisms and/or causes of the
arrhythmia.

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 VARRÓ ET AL.
The majority of cardiac arrhythmias are the result of
an enhanced proarrhythmic substrate combined with a
trigger (16). Enhanced heterogeneity of repolarization
and impaired impulse conduction represent typical ar-
rhythmia substrates (conditions that are prerequisites for
arrhythmia development) for severe tachyarrhythmia.
Impairment of impulse conduction can be caused by an-
atomical (FIGURE 2, A and B) (17) or functional (FIGURE
2C) (18) alterations. The process was described long
ago, first in the early twentieth century (19). Impulse con-
duction critically depends on the density and kinetics of
inward transmembrane ionic currents. Depolarization of
the resting membrane potential (RMP), for example,
reduces sodium and calcium inward currents and
strongly influences their kinetic properties. This can thus
slow impulse conduction and cause unidirectional or
bidirectional conduction block, and potentially reentry,
underpinning a wide range of cardiac arrhythmias.
As mentioned above, reentrant arrhythmias can be
caused by functional causes too, without an anatomically
well-defined myocardial damage (FIGURE 2C). This form of
reentry is more complex and could involve both impulse
conduction and repolarization heterogeneities (arrhythmia
substrate) as well as enhanced normal or abnormal automa-
ticity (trigger).
Reentrant arrhythmias are often initiated by an extrasys-
tole formed anywhere in the heart, acting as an arrhythmia
trigger (20, 21). Both arrhythmia substrate and trigger, like
an extrasystole [premature ventricular complex (PVC)], can
be promoted by pathological cardiac conditions (FIGURE
2), e.g., myocardial ischemia, heart failure (7), and genetic
diseases (22), or by adverse drug reactions (23). General
arrhythmia mechanisms include various cellular aspects,
e.g., transmembrane ionic currents, transporters, action
potential properties, and automaticity, which are the sub-
jects of this review. However, arrhythmia mechanisms at
the whole heart level are more complex, since they are
also determined by anatomical and structural properties,
impulse conduction, and intercellular communication
between myocardial and nonmyocardial cells, like fibro-
blasts. These factors are beyond the scope of the present
work, and the interested reader is referred to other reviews
(22, 24–34).
2. CARDIAC ACTION POTENTIAL
The cardiac action potential is a transmembrane poten-
tial change, with an amplitude ranging between 60 and
120 mV. It starts from a negative value, i.e., the resting
membrane potential (RMP) in working myocardial cells
or maximal diastolic potential in spontaneously beating
cells (1), ranging from 95 to 40 mV. As in other excita-
ble cells, the RMP is mainly defined by the conductance
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of inwardly rectifying K1 currents and can be roughly
estimated by the Nernst equation from the uneven distri-
bution of mainly K1 ions across the cell membrane. The
electrogenic ATP-dependent Na1-K1 pump also con-
tributes to the RMP, by exporting 3 Na1 and importing 2
K1 (35–38). In healthy conditions, the duration of the
action potential (APD) determines the effective refrac-
tory period (ERP), defined as the shortest time interval
needed before a new stimulus, or an early extrasystole,
can elicit another action potential. The relationship
between APD and ERP can be disrupted in pathological
conditions, for example, in hyperkalemia, resulting in
postrepolarization refractoriness (39).
In the context of the cardiac action potential, two
aspects should be emphasized. First, there is no such
uniform entity as “the cardiac action potential,” since its
shape, i.e., the time course of the transmembrane poten-
tial changes, differs in the various regions of the heart
(FIGURE 1), and therefore different action potentials
should be considered and discussed separately.
Second, there are significant interspecies differences
(40), even when action potentials are recorded from sim-
ilar regions of the heart. This is an important, and often
overlooked, issue, since many experimental results
have been obtained in small rodents, recently particu-
larly in transgenic mice.
In general, the cardiac action potential is divided into
five distinct phases (FIGURE 1). Phase 0 is the fast depo-
larization due to an abrupt increase in sodium influx, and
it is characterized by the upstroke velocity and can result
in an overshoot, i.e., the rapid change of potential from
the negative RMP to positive voltage values, reaching a
peak of up to 130 to 140 mV. The overshoot is fol-
lowed by a return to negative values, in a process called
repolarization, which includes phases 1, 2, and 3. Phase
1 is characterized by a transient and relatively fast repo-
larization brought about by a decrease in sodium influx
and a transient increase in potassium efflux and chloride
influx. Phase 2 consists of a long-lasting plateau, still at
depolarized voltage, during which the membrane poten-
tial remains almost constant or decreases slowly,
caused by a small net transmembrane current carried by
simultaneous calcium (and some sodium) influx and po-
tassium efflux. Phase 3 represents the large repolariza-
tion toward the diastolic potential, mostly due to
increased potassium efflux and decreased calcium and
sodium influx. Phase 4 represents the resting membrane
potential in diastole in working myocytes and the spon-
taneous depolarization in pacemaker cells. In cardiac
myocytes that do not beat spontaneously the voltage
remains stable at the RMP, whereas in cells exhibiting
automaticity the potential gradually changes toward the
positive values, in a process called spontaneous dia-
stolic depolarization. When the threshold potential is
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
reached, a new spontaneous action potential is gener-
ated, with a certain cycle length.
There are four common methods to record cardiac
action potentials:
1) Weidmann and Coraboeuf were the first to record car-
diac action potentials in dog ventricular muscle (41) and
later in dog Purkinje fibers, using the sharp glass capil-
lary-based microelectrode technique (42). The classical
cardiac cellular electrophysiological knowledge gained
by using this technique was elegantly summarized in
an early monograph entitled Electrophysiology of the
Heart by Hoffman and Cranefield (1), published in 1960,
which is still useful today. This technique is still consid-
ered one of the best for accurate cardiac action poten-
tial recordings and can be used for both single-cell and
tissue recordings. Its major advantages include 1) the
ability to accurately record very fast voltage changes
and 2) because of the very fine tip of the pipette, very
little diffusion takes place out of the pipette solution,
having negligible effects on the intracellular milieu.
However, since this technique has some limitations
(e.g., difficulties in maintaining a stable impalement for
extended periods of time), other methods have also
been developed and used widely.
2) In intact hearts, in in vivo animal experiments, or in clini-
cal studies, where the microelectrode technique is diffi-
cult to apply, monophasic action potential recording
can also be used, with either a suction electrode (43,
44) or a Franz catheter (45). With this technique,
recordings can be easily performed from multiple sites
simultaneously, and impalements/attachments are not
lost because of vigorous contractions, even in in vivo
or ex vivo conditions. However, rapid voltage changes
or action potential amplitudes and shapes cannot be
determined accurately.
3) Since the introduction of the patch clamp by Neher and
Sakmann (46–48), the whole cell configuration of this
technique has been widely used. In the current-clamp
mode, it can record action potentials from isolated myo-
cytes. Despite its widespread use, this technique has im-
portant limitations that should be emphasized. First,
measurements are performed in single isolated myo-
cytes or, occasionally, cell pairs, and it is uncertain how,
and to what degree, different ion channels are influ-
enced by individual enzymatic digestion during the isola-
tion procedure (49). Therefore, even if the recordings
show single-cell action potentials with a normal shape,
the function of the finely regulated ion channels can be
drastically altered from their original condition. Also, the
cell is dialyzed with the pipette contents, and its intracel-
lular composition will change. When carefully and delib-
erately applied, however, this point can also be
considered an advantage, as it allows control of the intra-
cellular milieu. It should also be emphasized that single
isolated myocytes are devoid of electrotonic interactions
from neighboring cells. Therefore, the stochastic
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opening/closing be-havior of ion channels has a more
profound effect on membrane potential than in well-
coupled tissue preparations (50). In addition, in multicel-
lular preparations part of the ionic currents are utilized to
depolarize neighboring cells during impulse propaga-
tion, and this can considerably reduce the action poten-
tial peak compared with single cells (51). Hence, action
potential measurements in single isolated myocytes
obtained with the patch-clamp technique should be
interpreted with caution and not directly extrapolated to
intact tissue.
4) The latest approach to recording cardiac action poten-
tials is the optical mapping technique, which uses volt-
age-sensitive dyes and allows simultaneous recordings
from multiple sites (52, 53). This technique is also excel-
lent for dynamic studies and for investigations of arrhyth-
mia mechanisms (54, 55). Disadvantages of this method
include the difficulty of calibration to millivolts, phototox-
icity, photodegradation, and photon scattering effects
(56). Also, the application of excitation-contraction
uncoupling compounds, e.g., blebbistatin, is necessary
to avoid motion artifacts (57). These compounds may
interfere with the experiments, since, e.g., blebbistatin
was reported to elicit anomalous electrical activities (58)
and prolongation of action potential duration (59), and in-
hibition of contraction will also decrease metabolic rate
at the concentrations needed for motion artifact red-
uction.
3. TRANSMEMBRANE ION CHANNELS AND
TRANSPORTERS IN THE HEART
The cardiac action potential is the voltage change
caused by ions flowing through transmembrane ion
channels, via their dynamic and simultaneous opening
and closing (11, 60). Therefore, before addressing differ-
ent regional action potential patterns, we describe the
various transmembrane ion channels that have been
reported to operate in the heart cells.
Transmembrane ionic currents in the heart are usu-
ally measured with the patch-clamp technique in
enzymatically isolated myocytes. This allows record-
ing and analysis of unitary currents through single
ion channels or all channels on the sarcolemma.
Before the introduction of the patch clamp, trans-
membrane current recordings were less accurate,
because of the lack of proper voltage control of the
preparation, and fast current changes and gating
kinetics were impossible to determine accurately
(61). Therefore, much of the knowledge gained
before the introduction of the patch-clamp technique
has had to be reevaluated, and some currents have
been renamed. To the interested reader, we recom-
mend an excellent monograph by Denis Noble, The
1087
 VARRÓ ET AL.

FIGURE 3. Schematic illustration of voltage-gated sodium (Nav) and potassium (Kv) channels. Top: topological models of Nav1.5 channel subunits and
their molecular assembly. Four domains (I–IV) of Nav a-subunits contribute to individual Nav channel formation. Middle: the activated and inactivated
Nav channel configurations. Bottom: the transmembrane topologies of Kv, inward rectifier (Kir), and two-pore domain (K2P) potassium channel subunits.

Initiation of the Heartbeat (62), which deductively
and briefly summarizes our knowledge before the
use of the patch-clamp technique.
It is important to note that a given ionic current, meas-
ured with the patch clamp, does not correspond to a
unique ion channel. Certain transmembrane ionic cur-
rents can be conducted by several different ionic chan-
nels (3, 5), e.g., inward rectifier potassium current (IK1) is
carried by inward rectifier potassium (Kir)2.1, Kir2.2,
Kir2.3, and Kir2.4 channels (5, 63) and tandem of pore
domains in a weak inward rectifying potassium channel
(TWIK)-related acid-sensitive potassium (TASK) channels
(64), whereas transient outward current (Ito) is carried by
voltage-gated potassium (Kv)4.3, Kv4.2, and Kv1.4 chan-
nels. In addition, certain channels like human ether-à-
go-go-related gene (hERG) have multiple isoforms
(hERG 1a and 1b) (65) with different gating kinetics and
drug sensitivities (66). This offers the possibility of phar-
macologically modulating specific channel isoforms
without interfering with others, and thus avoiding unde-
sirable side effects.
Recent advances in genetics and molecular biology
have made it possible to further elucidate the structure
of ion channels (FIGURE 3). It is widely known that
most transmembrane ion channels consist of multiple
subunits: a pore-forming a and modulatory accessory
subunits, which can modify channel gating and serve
as possible drug binding or phosphorylation sites (3, 5,
67, 68).
3.1. The Fast Inward Sodium Current
The fast inward sodium current (INa) is the most impor-
tant current for impulse conduction in cardiomyocytes,
with a diastolic potential more negative than 60 mV
(69), and is therefore particularly important in atrial, ven-
tricular, and Purkinje fiber myocytes. This current is re-
sponsible for the influx of Na1 during phase 0 of the
action potential (FIGURE 1 and FIGURE 4), and it is con-
ducted by voltage-gated sodium (Nav)1.5 channels,
encoded by the gene SCN5A coassembled with b1–4
(SCN1–4B)-subunits (70). The high-molecular-weight
pore-forming a-subunit contains four repeat domains (la-
beled I–IV); each domain consists of six transmembrane
segments (S1–S6), and the S4 segment is responsible
for voltage sensing (FIGURE 3). Special extracellular
regions (P loops) between the S5 and S6 segments of
the four domains form the structure that is responsible

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 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
FIGURE 4. Action potential and underlying ionic currents recorded
from human ventricular myocytes with the patch-clamp technique
applying human ventricular action potential as command pulses at 1
Hz stimulation frequency, in the absence of any sympathetic effects.
Inward rectifier potassium current (IK1), rapid (IKr) and slow (IKs) compo-
nents of delayed rectifier potassium current, transient outward current
(Ito), and L-type calcium current (ICa,L) were measured as difference cur-
rent following application of selective channel inhibitors. INaL, late so-
dium current. Unpublished data from our laboratory at the Department
of Pharmacology and Pharmacotherapy, University of Szeged.
for the ion selectivity of the channel. The region that
links domains III and IV contains the inactivation gate
that “plugs” the channel pore after prolonged activation
(FIGURE 3). A detailed, comprehensive review on the
cardiac sodium channel structure has been published
recently (71). Nav1.5 channels open, within a fraction of a
millisecond, at potentials more positive than 60 mV,
with strong voltage dependence. Since channel density
is high, they carry a large inward current, with an ampli-
tude of >100 pA/pF. They also inactivate very rapidly at
voltages more positive than 80 mV (at 10 mV with
time constant s1 of 0.6 ms and s2 of 4 ms) (72), with a
half-inactivation between 60 and 70 mV. Nav1.5
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channels can recover from inactivation with a time con-
stant of 2–20 ms at negative voltages (69, 73, 74). The
exact kinetics of their inactivation and recovery are com-
plex and still not fully understood. So far, multiple inacti-
vation kinetics and recovery kinetics from inactivation
have been described (12, 69, 75–77).
In addition to this fast component, slow inactivation,
occurring over hundreds of milliseconds, has been
described (12, 13, 78) and attributed to late openings of
Nav1.5 channels (79). Recently, a new term, “late sodium
current” (INaLate), has been used to refer to this current,
which, although small in amplitude (<0.5% of the peak
INa) (79, 80), nonetheless represents an important sus-
tained depolarizing current during phase 2, thus playing
a role in maintaining the relatively long plateau of the
cardiac action potential (FIGURE 4) (78). This INaLate is
more sensitive to tetrodotoxin (TTX) and other sodium
channel inhibitors (81) than the peak INa (82).
As a steady-state component of INa, a so-called “win-
dow sodium current” in the voltage range from –65 to –
15 mV based on a different mechanism than the slow
inactivation was also suggested earlier by Attwell et al.
(9). This window current was considered to be caused
by the overlap between the steady-state activation and
inactivation curves. At present, it is still not clear whether
such a window current exists, or if the measured overlap
is due to an ultraslow inactivation or ultraslow recovery
from inactivation when this window current is deter-
mined. To better understand the nature of the sodium
current during the plateau phase of the action potential,
the possible involvement of sodium channels other than
the Nav1.5 channel, which is considered to be the major
cardiac sodium channel, was also suggested in several
studies (83–88). As an example, Nav2.1 a-, b1-, and b2-
subunits are highly expressed in human atrial and ven-
tricular cells and Purkinje fibers (84, 85) even if their
function has not been explored yet. The expression of
various neuronal sodium channel subtypes, e.g., Nav1.1,
Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.8 (encoded by
SCN1A, SCN2A, SCN3A, SCN4A, and SCN10A genes,
respectively), has been described in different cardiac
preparations (89), but again their functional roles are not
fully understood (3, 5, 85, 86, 90). Mishra et al. (86)
reported that in failing dog and human hearts neuronal
Nav1.1 channels were upregulated and provided signifi-
cant INaLate, whereas another recent study (91) showed
significant upregulation of Nav1.8 channels in failing
human hearts. In addition, selective inhibition of this
Nav1.8 current by A-803467 (92) abolished arrhythmo-
genic Ca21 sparks that were attributed to enhanced in-
tracellular Ca21 load due to increased INaLate. Mutations
in the Nav1.8 encoding gene, SCN10A, were reported in
patients with atrial fibrillation (AF) (88) and also predis-
posed to sudden cardiac death (83). Therefore, it is
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FIGURE 5. Regional and subcellular distribution of SCN5A/voltage-gated sodium channel (Nav)1.5 in the heart and cardiomyocytes. Left: the expres-
sion levels of SCN5A in different regions of the heart. Expression of SCN5A is highest in the atrioventricular (AV) bundle, His bundle, and right (RBB)
and left (LBB) bundle branch (dark green). SCN5A is broadly expressed in right (RA) and left (LA) atria and right (RV) and left (LV) ventricle with an epi/
endo gradient in the ventricles. SCN5A is absent from the central sinoatrial node (SAN) and atrioventricular node (AVN). Right: the localization of Nav1.5
with specific regional partner proteins in the microdomains of a cardiomyocyte: intercalated disk (ID), lateral membrane (LM), and T tubules. The sodium
current at the ID is larger than the sodium current at the LM. Reproduced from Ref. 94 with permission.

clear that further studies are needed to elucidate the
role of neuronal Na1 channels in normal and diseased
heart (93).
It is known that Nav1.5 channel expression varies in
the different regions of the heart, showing a high level of
expression in the specialized conduction system, atria
and ventricles, while being absent in the central sinus
and atrioventricular nodal tissues (FIGURE 5). Also,
Nav1.5 channels gather in clusters and associate with
accessory subunits and partner proteins, forming
region-specific macromolecular complexes (95). They
are not evenly distributed within the myocyte (96). The
current densities are large in the intercalated disk area
and smaller in the lateral membrane (96, 97). The com-
plex nature and the observed regional differences in so-
dium channel expression, as well as the functional
significance of Nav1.5 interactions with partner proteins,
justify further studies to better understand the patho-
physiology of diseases associated with Nav1.5 dysfunc-
tion, including inherited sodium channelopathies (94,
98).
The function of INa is regulated by intracellular calcium
homeostasis in a complex way that involves multiple
accessory proteins (99). Calmodulin (CaM), the ubiqui-
tous Ca21-sensing protein, plays a central role in intra-
cellular Ca21 concentration ([Ca21]i)-dependent INa
function alterations by modulating fast inactivation of INa
(100). Recent data suggest that CaM facilitates the re-
covery of the sodium channel from inactivation by inter-
acting with its inactivation gate in a Ca21-dependent
fashion (101). The different binding sites of CaM on the
sodium channel are important to understand the mecha-
nisms linked to disease-associated sodium channel
mutations (102–104). In addition to CaM, Ca21/calmodu-
lin-dependent kinase II (CaMKII) has been shown to
modify INa function in a Ca21-dependent manner.
CaMKII phosphorylation regulates cardiac Na1 channels
by slowing their recovery from inactivation (105, 106).
This results in reduced availability of fast INa at a high
rate with enhanced late INa (106). The latter contributes
to prolonged repolarization and enhanced arrhythmia
susceptibility (106, 107) often seen in heart failure, where
CaMKII activity is enhanced (107).
In addition to TTX, INa is blocked, although not sel-
ectively, by a wide range of antiarrhythmic drugs, e.g.,
lidocaine, mexiletine, quinidine, disopyramide, and

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 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS

FIGURE 6. Tissue-specific (human) cardiac atrial, Purkinje fiber, and ventricular action potentials and the underlying ionic currents in different action poten-
tial phases, indicating their pharmacology and modulation. Black arrows indicate inward and yellow arrows indicate outward current. The contributions of dif-
21
ferent currents to the action potentials are indicated below, with a time course adjusted to the action potential. CaM, calmodulin; CaMKII, Ca -calmodulin
kinase II; hERG, human ether-à-go-go-related gene; IK1, inward rectifier potassium current; IK,Ach, acetylcholine-activated potassium current; INa, sodium current;
ICaL, L-type calcium current; ICaT, T-type calcium current; If, funny/pacemaker current; Ito, transient outward current; IKCa, calcium-activated potassium current;
IKr, IKs, and IKur, rapid, slow, and ultrarapid components of delayed rectifier potassium current; Kir, inward rectifier potassium channel; KV, voltage-gated potas-
sium channel; NaV, voltage-gated sodium channel; TASK, Tandem of pore domains in a weak inward rectifying potassium channel (TWIK)-related acid-sensi-
tive potassium channel; TTX, tetrodotoxin.

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 VARRÓ ET AL.
flecainide (FIGURE 6) (108, 109) in a frequency-depend-
ent manner. It has recently been reported that certain
drugs like ranolazine and GS967 selectively inhibit
INaLate (110, 111). Therefore, these compounds would be
particularly effective for long QT (LQT) syndromes, heart
failure (HF), or hypertrophic cardiomyopathy (HCM) (110).
On the other hand, late INa can be pharmacologically
augmented by veratrine (112), veratridine, and ATX (113).
Genetic mutations that alter INa function can lead to
severe, potentially lethal, conditions and have been
shown to play a significant role in a wide array of inher-
ited channelopathies (for recent reviews see Refs. 94,
114–117). As an example, loss-of-function SCN5A muta-
tions lead to a reduced INa peak, thus slowing impulse
conduction and possibly causing conduction block.
These mutations have been identified in 20% of
patients with Brugada syndrome (BrS) (118) as well as in
patients with sick sinus syndrome and progressive car-
diac conduction defect (119–121). On the other hand,
gain-of-function SCN5A mutations have been shown to
play key roles in congenital LQT3 syndrome (122). In
some cases of familial AF, both loss-of-function and
gain-of-function SCN5A mutations have been identified
(123, 124).
The late sodium or window current, irrespective of
its basic mechanism or molecular background, is particularly
important in arrhythmogenesis (125). As an example, in
HF and in HCM, INaLate is augmented (126, 127). Since
this current is an important contributor to the action
potential plateau phase, its enhancement prolongs
repolarization and increases repolarization heterogene-
ity (110, 128). In addition, by increasing intracellular so-
dium concentration, it also increases intracellular
calcium concentration, via the Na1/Ca21 exchanger
(NCX). This can evoke arrhythmogenic triggered activity
such as early and delayed afterdepolarizations (EADs
and DADs, respectively) (129–131), discussed below in
this review. Both triggered automaticity and enhanced
dispersion of repolarization are considered major mech-
anisms in arrhythmogenesis, and their reduction is a
major aim in antiarrhythmic drug development.
3.2. The Transient Outward Current
The main channels providing the transient outward po-
tassium current (Ito) in human and dog ventricular muscle
are Kv4.3 and Kv4.2 pore-forming a-subunits coas-
sembled with KChIP2 and DPP auxiliary subunits (85)
encoded by KCND3, KCND2, and KCNIP2 and DPP6/10
genes, respectively (132–134). Kv1.4 a channel subunits
(encoded by KCNA4) are also expressed with marked
regional and interspecies dependence, making up 10–
20% of Ito density in humans (135, 136). Accordingly, in
humans (unlike in dogs), in addition to the rapid
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component (sfast 50–100 ms), the Ito recovery from
inactivation also has a component with a slow recovery
time constant (on the order of seconds) that is character-
istic of the Kv1.4 channels (137). It is interesting that in
rabbit ventricle the Ito current is primarily conducted by
Kv1.4 channels (138). However, the functional role of this
channel in rabbits is still unclear, as it is inactivated most
of the time at their physiological heart rate, which is
quite high. In humans, both Kv4.3 and Kv1.4 channels can
have functional roles, particularly in the frequency-de-
pendent modulation of the APD during both different
constant or following abrupt changes in cycle lengths
during electrical restitution (i.e., following extrasystoles
with different coupling intervals). In addition, there are
mRNA expression studies (85, 139) supporting the possi-
bility that the Kv1.7 channels also have a functional role
for Ito in human atria and ventricles. However, because
of the relative paucity of data regarding Kv1.7 channels
in the heart, further research is needed to properly eluci-
date these issues.
Human and dog Ito start activating at membrane
potentials more positive than 30 mV, rapidly reaching
peak values (within 1–2 ms) and then inactivating with a
double-exponential time course (sfast 5 ms, sslow 25
ms) (140). The Kv4.3 channel-mediated Ito, unlike Kv1.4,
recovers rapidly from inactivation in the membrane volt-
age range of 60 to 80 mV, with a time constant of
50 ms (137). In dog and human Purkinje fibers, Kv3.4
channels were also described to contribute to Ito, with
different kinetic properties compared with Kv4.3 chan-
nels (141). This raises the possibility for fine-tuning of fre-
quency-dependent modulation of repolarization
dispersion between Purkinje fibers and ventricular mus-
cle (142).
The transient outward potassium current and the
fast inactivation of INa are important contributors to the
early/fast repolarization of the action potential (phase
1) (137, 143) (FIGURE 4). Phase 1 repolarization and Ito
are more prominent in Purkinje fibers and atrial, mid-
myocardial, and subepicardial ventricular muscle (137),
but they are small, or nonexisting, in subendocardial
ventricular cells and sinoatrial (SA) and atrioventricular
(AV) nodal cells (137). Interestingly, phase 1 repolariza-
tion and Ito are not present in guinea pig ventricular
myocytes (144, 145). Also, it has been reported that in
mouse ventricle Ito is small and action potential is long
after birth and later the action potential shortens as Ito
develops in adult mice (146, 147). The impact of Ito on
the shape of the action potential waveform is complex.
In addition to its role in phase 1, Ito also modulates the
voltage level of the plateau, and consequently it has
an indirect influence on activation, inactivation, and
deactivation of several other transmembrane ionic cur-
rents that operate during the plateau phase. Since Ito,
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
similarly to INa, has activation, deactivation, and inacti-
vation properties, it was also suggested that a window
Ito current may be generated, in the membrane poten-
tial range from 35 to 10 mV. This window current
would also contribute to the final repolarization (140). It
was also reported that interaction of DPP10a with
Kv4.3 channels results in a sustained current compo-
nent of human atrial Ito that can participate in the late
repolarization phase (148). However, despite its poten-
tial importance, it is difficult to validate or disprove the
existence of such current, since selective inhibitors are
lacking. This suggests the need for further research to
clarify this issue. Ito is a typical transmembrane ionic
current that can be attributed to the function of a wide
variety of distinctly different potassium and also chlo-
ride ion channels (137). Although the role of Ito in
arrhythmias is not well defined, it definitely plays a role
in Brugada syndrome (117, 149), where a reduced
expression level of the auxiliary Ito subunit, KChIP2, in
females most likely underlies the male phenotypic pre-
dominance (150, 151). The stronger epicardial Ito in
males could further aggravate the consequence of
impaired INa in Brugada patients; in this case, inhibition
of Ito would be beneficial. Multiple nonselective Ito
inhibitors have been reported (FIGURE 6): 4-aminopyr-
idine (4-AP), in millimolar concentrations (152); quini-
dine, flecainide, and chromanol 293B, in micromolar
concentrations (140, 152); and phrixotoxin, in nanomo-
lar concentrations (153). However, a selective Ito inhibi-
tor is still lacking. This could constitute a potential
treatment in atrial fibrillation, by increasing APD and
consequently ERP, in atrial but not or less in ventricular
tissue (154). An activator for Ito was also reported hav-
ing effect on canine ventricular but not atrial myocytes
(155).
Ito is downregulated in HF (156–159), HCM (160), and
diabetes mellitus (161, 162), possibly contributing to
repolarization prolongation in these pathological set-
tings. Recently, it was shown that Kv4.3 (fast Ito) and
Kv1.4 (slow Ito) were expressed differently in normal
and failing hearts, thus contributing to arrhythmogenic
regional heterogeneity in action potential waveforms
(101). It was also demonstrated that a slowing of phase
1 repolarization, which can be due to the decreased Ito
often observed in failing hearts (163–165), decreases
the driving force of Ca21 through L-type calcium chan-
nels, and it can result in potentially arrhythmogenic
asynchronous Ca21 release from the sarcoplasmic
reticulum (SR) (166). Ito is subject to a- and b-adrener-
gic regulation, both decreasing Ito via the PKA and
PKC pathways (167), whereas CaMKII has been shown
to increase Ito (167).
Thyroid-stimulating hormone and thyroid hormones
have been shown to modulate Ito (168, 169), thus making
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Ito an important contributor to repolarization abnormal-
ities in altered thyroid status.
3.3. Inward Calcium Current
The inward calcium current (ICa) in the heart was first
described by Reuter (170), and it has two major types
(171, 172). The most abundant type is the L-type calcium
channel (Cav1.2), which conducts current through the
pore-forming a-subunit (a1) encoded by the CACNA1C
gene (85). The a1-subunit consists of 2,000 amino
acids, organized into four repeat domains (I–IV), each
containing six transmembrane segments (S1–S6) (173).
The S4 transmembrane helix from each domain collec-
tively constitute the voltage sensor of the channel (173).
A region called the “P loop” connecting the S5 and S6
segments is responsible for the Ca21 selectivity of the
pore region (174). The pore-forming subunit coassem-
bles with the extracellular a2d and intracellular b auxil-
iary (predominantly b2 in cardiac tissue) subunits that
modulate kinetics, gating, and trafficking properties of
the channel (175–177). Inward L-type Ca21 current (ICa,L)
has a very rapid activation (14) and is particularly impor-
tant for excitation-contraction coupling (178), since it
serves as a trigger for the calcium-induced calcium
release (CICR) (179) from the SR and as a source of
extracellular calcium when needed. In addition, ICa,L
plays a fundamental electrophysiological role in main-
taining the plateau phase of the action potential
(FIGURE 4) and in the depolarization of SA and AV nodal
cells (180). In these cell types, ICa,L is the main contributor
to impulse conduction; therefore its impairment pro-
longs the PQ interval and can result in AV node conduc-
tion block. In addition, since ICa,L provides depolarizing
current, its decrease would reduce the spontaneous fre-
quency of these cells. In AV nodal cells, this shift in
threshold potential also contributes to the slowing of AV
impulse conduction. The inactivation kinetics of L-type
ICa (sfast 2–8 ms, sslow 30–100 ms) depend not only
on membrane voltage but also on the intracellular Ca21
concentration (14, 15, 181–184), which is dynamically
changing during the action potential. The recovery from
inactivation is complex and strongly depends on volt-
age. At 40 mV it can be characterized by an exponen-
tial time course ranging between 30 and 60 ms with
sfast = sslow (14, 185). Importantly, the recovery kinetics
can be faster in ventricular and Purkinje fibers, which
have a resting potential around 80 mV. The ICa,L was
originally called slow inward current (Isi), since with the
old experimental methods, before the introduction of
single-cell voltage clamp, a relatively slow ICa activation
was measured (170, 186). Later, with more advanced
voltage-clamp techniques, the proper fast activation
kinetics could be determined (187).
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Table 1. Changes of genes, channel/transporter proteins, and ionic currents in various genetic disorders
Genetic Disorder Gene Protein Ionic Current/Function

Trigger

CPVT 1 RYR2 Ryanodine receptor SR Ca21 release

CPVT2 CASQ2 Calsequestrin : SR Ca21 release

Inherited sinus bradycardia SCN5A Nav1.5 ; INa

Sick sinus syndrome HCN4/SCN5A HCN4/Nav1.5 ; If/INa

Familial inappropriate tachycardia HCN4/SCN5A HCN4/Nav1.5 : If/INa

Substrate

Brugada syndrome SCN5A Nav1.5 ; Impulse conduction

ARVC (Naxos disease) Desmosome protein ; Impulse conduction

LQT1 KCNQ1 KCNQ1 (Kv7.1) ; IKs

LQT2 KCNH2 hERG (Kv11.1) ; IKr

LQT3 SCN5A Nav1.5 : INa

LQT4 (ankyrin-B syndrome) ANK2 Ankyrin-B Multichannel interactions

LQT5 KCNE1 KCNE1 (minK) ; IKs

LQT6 KCNE2 KCNE2 (MiRP1) ; IKr

LQT7 (Andersen–Tawil syndrome type 1) KCNJ2 Kir2.1 ; IK1

LQT8 (Timothy syndrome) CACNA1C Cav 1.2 : ICa

LQT9 CAV3 Caveolin 3 : INa

LQT10 SCN4B Nav 1.5 b4 : INa

LQT11 AKAP9 AKAP-9 (yotiao) ; IKs

LQT12 SNTA1 a1-Syntrophin : INa

LQT13 KCNJ5 Kir3.4 (GIRK4) ; IKACh

LQT14 CALM1 Calmodulin Multichannel interactions

LQT15 CALM2 Calmodulin Multichannel interactions

LQT16 CALM3 Calmodulin Multichannel interactions

SQT1 KCNH2 HERG : IKr

SQT2 KCNQ1 KVQT1 : IKs

SQT3 KCNJ2 Kir2.1 : IK1

SQT4 CACNA1C Cav a1 ; ICa,L

Continued

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 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS

Table 1.—Continued
Genetic Disorder Gene Protein Ionic Current/Function

SQT5 CACNB2b Cav b2b ; ICa,L

SQT6 CACNA2D1 Cav a(2) d-1 ; ICa,L

SQT7 SLC22A5 OCTN2 Carnitine deficiency

SQT8 SLC4A3 AE3 ; Cl /HCO3 exchanger function

Familial AF KCNQ1 KVLQT1 ; IKs

KCNE2 MIRP1 ;?

KCNJ8 Kir6.1 : IK,ATP

AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular cardiomyopathy; CPVT, catecholaminergic polymorphic ventricular tachycardia; ICa, calcium
current; ICa,L, L-type Ca21 current; If, funny/pacemaker current; IKACh, acetylcholine-activated potassium current; IK,ATP, ATP-sensitive potassium current;
IKr, rapid component of delayed rectifier potassium current; IKs, slow component of delayed rectifier potassium current; IK1, inward rectifier potassium cur-
rent; INa, sodium current; LQT, long QT syndrome; SQT, short QT syndrome; SR, sarcoplasmic reticulum.

ICa,L is modulated (FIGURE 6) by cAMP-dependent
phosphorylation and other factors, including intracellular
Ca21 levels (15). It has been shown that CaM supports
both inactivation and facilitation of ICa (188). The intracel-
lular Ca21 enhances ICa via CaMKII, involving direct
phosphorylation of L-type Ca21 channels (189, 190) inde-
pendently of cAMP via PKA (191) involving Rad, a mono-
meric G protein that closely interacts with Cav1.2 (192).
ICa,L can be effectively blocked (FIGURE 6) by Cd21, ve-
rapamil, and diltiazem, but the inhibition with these
drugs is not selective (193–195). Dihydropiridines, e.g.,
nifedipine (196) and nisoldipine (197), are more selective
ICa,L blockers, but they may be sensitive to light (198).
Pharmacological activation of ICa,L is also possible by
Bay K8644 (FIGURE 6) (199).
The ICa,L has key roles in several diseases like HF
(200), HCM (27), AF (201), and myocardial ischemia and
in other pathophysiological conditions, such as the de-
velopment of EADs, DADs, (202–204) and cardiac is-
chemia-reperfusion (205), discussed in more detail in
other parts of this review.
A gain-of-function G406R mutation of the Cav1.2 chan-
nel causes type 8 of congenital LQT syndrome, also
called Timothy syndrome (TABLE 1). This disease is
characterized by slower inactivation of ICa,L (206–208)
and by the fact that small clusters of Cav1.2 channels
have a larger probability for coordinated opening and
closing (“coupled gating”) (209), thus leading to tachyar-
rhythmia and congenital heart defects (ductus arterio-
sus, ventricular septal defect, Fallot tetralogy, HCM)
(210).
The second type is the T-type calcium current (ICa,T),
for which significantly less data are available. Its func-
tional role in atrial and ventricular cells and Purkinje
fibers is still unclear. However, it plays an important role
in the SA and AV nodal cells (211), where it makes a sig-
nificant contribution to the pacemaker function. This cur-
rent is conducted by Cav3.1 and Cav3.2 channels,
encoded by CACNA1G and CACNA1H genes, respec-
tively (212). ICa,T activates at more negative membrane
potentials than ICa,L, and its overlap with INa makes it diffi-
cult to study (172). ICa,T can be inhibited by low concen-
trations (100–200 mM) of Ni21 (172) and by the organic
compound mibefradil, which was developed with the
aim of decreasing elevated heart rate (213).
3.4. Delayed Rectifier Potassium Currents
Before the introduction of the patch-clamp technique, a
slowly activating current carried by K1 was recorded
during the plateau phase. This current was named the
delayed rectifier potassium current (Ix1/2). Later, by apply-
ing single-cell patch-clamp technique, Sanguinetti and
Jurkiewicz (214) showed that this delayed rectifier out-
ward potassium current can be separated into a rapid
(IKr) and a slow (IKs) component. Molecular biological
studies also confirmed that these two IK components are
conducted by distinctly different ion channels.
3.4.1. The rapid delayed-rectifying potassium
current.
The rapid delayed rectifier outward potassium current
(IKr) is conducted by the Kv11.1 pore-forming a-subunit,
also called hERG in humans (human ether-à-go-go
related gene), which is associated with various acces-
sory b and possibly other subunits (85, 215, 216).

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 VARRÓ ET AL.
Similarly to other Kv channel pore-forming a-subunits,
Kv11.1 consists of six transmembrane segments (S1–S6)
and the functional channel contains four a-subunits
(FIGURE 3) (217). The Kv11.1 hERG a-subunit has two iso-
forms (a and b), which are different in terms of gating
and drug sensitivity (65, 66). The wide variety of interact-
ing accessory b-subunits include MinK (human minimal
potassium ion channel), MiRP1 (mink-related peptide 1),
and MiRP2, MiRP3, and MiRP4 proteins encoded by
KCNE1, KCNE2, KCNE3, KCNE4, and KCNE5 genes,
respectively (85, 215). Initially, it was suggested that
MiRP1 interacted with hERG (Kv10.1) to form IKr channels
(218). This is due to the fact that when hERG (Kv11.1) a
channel subunits were expressed alone in HEK cells, a
very rapidly activating steady-state-like current was
observed, and only coexpression with MiRP1 resulted in
currents that resembled native IKr. On the basis of this
observation MiRP1 was considered the most important
accessory subunit to form the native IKr channel.
However, later studies indicated very low levels of
KCNE2 expression in human heart, whereas genes of
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other b-subunits like MinK, MiRP2, MiRP3, and MiRP4
were abundantly expressed in human atrial and ven-
tricular tissue and Purkinje fibers (85). Coexpression of
the b- and hERG a-subunits produced currents with
kinetics similar to those native currents that can be
recorded in different species including human (219,
220). However, the exact role of these b and other
possible accessory subunits, how they regulate IKr,
and whether they are responsible for the observed
species-dependent differences and drug sensitivities
are unclear at present and need to be elucidated in
the future. IKr activates in a voltage-dependent man-
ner, with an activation s of 31 ms at 130 mV in human
ventricular myocyte (221). It also slowly deactivates
(222) in a voltage-dependent manner; its deactivation
can be fitted by a double exponential with sfast of 600
ms and sslow of 6,800 ms at 40 mV. The ratio of the
amplitudes of the fast and slow components increases
at more negative potentials. IKr exhibits a peculiar, very
rapid, inactivation (223–225), which starts even before
it activates.
FIGURE 7. The role of the slow component of the delayed
rectifier potassium current (I ) in the repolarization in dog
Ks
ventricular papillary muscle (A–C) and in dog single ventricu-
lar myocyte (D). In A, action potential duration (APD) is not,
or minimally, changed after full I inhibition by 100 nM L-
Ks
735,821 without external sympathetic stimulation. In B, in the
same preparation full IKs inhibition elicited significant prolon-
gation of repolarization in a preparation where the rapid
component of the delayed rectifier potassium current (IKr)
was inhibited by E-4031 and late sodium current (I ) was
NaLate
augmented by veratrine. In C, transmembrane current
recordings show that during a short (150 ms) voltage pulse
very little I develops, but when pulse duration was
Ks
increased to 500 ms significant IKs developed, explaining
the lack and significant changes of APD after I inhibition in
Ks
A and B. (Reproduced from Ref. 228 with permission.) In D,
the result of a representative experiment is shown in dog
ventricular myocytes. In the baseline (control) situation, small
short-term APD variability and normal APD were recorded
that did not change significantly after I inhibition by chro-
Ks
manol 293B. Additional application of I block by almoka-
Kr
lant increased both APD and short-term APD variability
illustrated by the Poincare
plot, which was substantially fur-
ther lengthened and increased by additional IKs inhibition,
respectively. (Reproduced from Ref. 255 with permission.)
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
During the action potential in early plateau and in
phase 3, IKr channels rapidly recover from inactivation
and they reopen as voltage changes toward more nega-
tive values, and deactivation progresses. Accordingly, de-
spite the rapid activation of the current during the plateau
phase, a relatively tiny current develops that gradually
increases and decreases during phase 3 repolarization
(FIGURE 4); therefore it is a crucially important current to
secure repolarization.
Since IKr deactivates slowly, it does not have time to
fully deactivate during an action potential. Therefore, a
residual and gradually decreasing outward current can
still flow through this channel, thus shortening the next
action potential when diastolic interval is relatively short,
i.e., during fast heart rate or during an early extrasystole
(222). Consequently, IKr is considered a key player in fre-
quency-dependent APD regulation, and it can influence
the pacemaker function as well (226).
IKr can be blocked by specific compounds in the sub-
micromolar or micromolar range (e.g., dofetilide and E-
4031) (FIGURE 13 and FIGURE 7), causing a marked pro-
longation of the action potential (227, 228). It was
reported that this current can be modulated (FIGURE 6)
by endogenous substances like endothelin, which sup-
presses IKr (229). Decreased IKr was also observed after
a1- and b1-receptor activation, linked to the PKC and PKA
pathways, respectively (230–232). There are also some
compounds known to enhance IKr (FIGURE 6).
In pathophysiological conditions, IKr can change. In hy-
pokalemia, the magnitude of the current decreases
(233–235), thus making the heart vulnerable to torsades
de pointes (TdP) arrhythmia, especially in the presence
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of IKr-blocking drugs (236). The effect of ischemia on IKr
is complex, since acidosis was reported to decrease IKr
(237, 238), particularly by inhibition of the hERG1b iso-
form of the channel (239), but hyperkalemia can
increase (234, 235) the current—and both are present in
ischemia. Reduced IKr was also reported in the infarcted
zone in dog myocytes (240). In HF, IKr is generally con-
sidered downregulated (241), even if different studies
report sometimes contradictory results.
Loss-of-function mutations in hERG channel can cause
congenital long QT syndromes (237, 242, 243), whereas
gain-of-function mutations lead to short QT syndromes
(244–246) (TABLE 1).
3.4.2. The slow delayed-rectifying potassium
current.
The slow component (IKs) of IK is carried by the Kv7.1 chan-
nel, consisting of a pore-forming a-subunit (FIGURE 3)
(217), encoded by the KCNQ1 gene, that coassembles
with various MinK, MiRP1, MiRP2, MiRP3, MiRP4, and
other accessory subunits, encoded by KCNE1, KCNE2,
KCNE3, KCNE4, and KCNE5 genes, respectively (85,
215). MinK was the first b accessory protein (247, 248)
that was identified for the Kv7.1 channel, but later the im-
portance of other b-subunits (e.g., MiRP1, MiRP2, MiRP3,
MiRP4) was recognized, suggesting that this variability in
b-subunits may serve as the basis for the marked inter-
species variability in native IKs properties (67, 68). In
guinea pig, the amplitude of IKs is large [(3, 214, 249), and
its kinetics differs from those measured in rabbit (250,
251), dog (228) or human (252, 253) ventricular muscle. In
FIGURE 8. A–C: influence of slow compo-
nent of delayed rectifier potassium current
(IKs) inhibition by chromanol 293B (A), sym-
pathetic stimulation by isoproterenol (ISO,
B), and combination of IKs block and sympa-
thetic stimulation (C) in isolated dog cardiac
Purkinje cells. Note that in control (Ctl) con-
dition plateau phases of the Purkinje cells
are at more negative voltage than the acti-
vation threshold of IKs, and accordingly IKs
inhibition did not change repolarization. In B,
isoproterenol shifted the action potential
plateau voltage to more positive values
because of substantially increased IKs. D: in
this situation, IKs inhibition substantially len-
gthened repolarization as shown in C. (Rep-
roduced from Ref. 157 with permission.)
1097
 VARRÓ ET AL.
most species, IKs activates slowly and in a voltage-de-
pendent manner, at potentials more positive than 30
mV, with s of several hundred milliseconds to seconds
(254). The current deactivates rapidly, except in guinea
pigs, in a voltage-dependent manner, with s of <200 ms
at 40 mV (253). The density of IKs during the plateau of
a normal action potential is small (FIGURE 4), because of
its slow activation. Therefore, its contribution to repolari-
zation without b-adrenergic stimulation is minimal, except
in guinea pig (FIGURE 7A). However, normal physiologi-
cal conditions always involve some level of sympathetic
tone that increases basal IKs density (255). In addition,
when plateau voltage is enhanced by the elevated sym-
pathetic tone, more IKs develops and contributes more to
repolarization (256) (FIGURE 8). IKs is a critical contributor
to the repolarization reserve (257, 258). According to this
concept, cardiac repolarization is provided by multiple
redundant ionic currents that can compensate for each
other’s loss of function. Therefore, a dysfunction of a sin-
gle repolarizing current does not necessarily cause a
measurable effect on repolarization. However, congenital
or acquired defects in the function of multiple currents
can be additive. As shown in FIGURE 7, A and D, IKs block
at baseline does not prolong ventricular repolarization
and does not increase short-term variability of APD, which
is a recently suggested predictive parameter of proar-
rhythmic risk (259). However, after IKr block (by E-4031 or
almokalant), IKs inhibition significantly prolongs repolariza-
tion (FIGURE 7B) and increases short-term variability of
repolarization. At longer repolarization duration, induced
either by IKr block or by longer voltage pulses (FIGURE 7,
B and C), more IKs develops and, as a negative feedback
mechanism, it can limit excessive APD lengthening (221,
228, 260). Although some studies have reported IKs in
atrial tissue (261, 262), and both KCNQ1 and its accessory
subunits are expressed in the atria at levels similar to
those in the ventricle (263), the presence and role of IKs in
human and canine atrial including sinoatrial node (SAN)
cells are still unclear. Assuming similar IKs kinetics in atria
and ventricles, less IKs activation can be expected in atrial
myocytes, since the plateau phase is shorter and it devel-
ops at more negative voltages than in ventricular myo-
cytes. One may speculate that at very rapid rates (e.g.,
during atrial fibrillation or flutter) the continuous presence
of a very tiny IKs current during the action potential, due to
frequent channel opening and slow recovery compared
with the diastolic interval, may produce a steady-state-
like sustained outward current, which may have a role in
modulating the resting membrane potential, the pace-
maker activity, or even the APD. To resolve these contro-
versies, further research is needed.
IKs is regulated by endogenous substances (FIGURE 6).
Progesterone, and cAMP/PKA-dependent phosphorylation
via the Yotiao accessory subunit protein (264), increases IKs
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(255, 265). PKC has a biphasic influence, increasing IKs after
short-term application and decreasing IKs after long-term
application (266). It was also reported that the PKC-medi-
ated IKs augmentation was PKC isoform dependent (267,
268). Drugs are available to inhibit (228) and to activate
(269) IKs (FIGURE 6). Hypokalemia and elevated intracellular
Ca21 enhance and hyperkalemia decreases IKs (235, 270).
Diseases like heart failure (7) and diabetes mellitus
(271) and genetic mutations (LQT1) (114, 149) or drugs
(228) can reduce IKs channel expression, and, as a con-
sequence, the reserve repolarizing current provided by
IKs would be diminished.
This scenario can be further aggravated when intracel-
lular cAMP is elevated, and cAMP-dependent phospho-
rylation enhances L-type ICa. Since ICa,L is an inward
current, which prolongs repolarization, the negative feed-
back function of impaired IKs cannot sufficiently limit ex-
cessive APD prolongation. Therefore, dispersion of
repolarization and propensity for life-threatening arrhyth-
mia can increase (272). Genetic mutations can also lead
to gain of function of IKs, resulting in increased current.
The mutations have been shown to have concomitant
effects in sinoatrial, ventricular, and atrial cardiomyocytes
and lead to complex clinical phenotypes (273–281).
3.5. Inward Rectifier Potassium Current
Inward rectifier potassium current (IK1), similarly to Ito, is a
current that is carried by several channels (282), even if
this fact is sometimes overlooked when its behavior is
discussed (283). Therefore, the definition of IK1 needs
I (pA)
800
400
V (mV)
-120 -100 -80 -60 -40 -20 20
Kir2.3 Untransfected cell
Kir2.1 -400
-800
Kir2.2
-1200
FIGURE 9. Distinct current (I)-voltage (V) relations of inward recti-
fier potassium (Kir)2.x channels expressed in HEK293 cells. Different
colors depict ramp ( 100 to 0 mV)-generated, barium-sensitive cur-
rents in cells expressing Kir2.x channels. The current in an untrans-
fected cell is shown in green. (Reproduced from Ref. 63 with
permission.)
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
particular care. Here we define IK1 as a current con-
ducted by channels consisting of Kir2.1, Kir2.2, Kir2.3, and
Kir2.4 pore-forming a-subunits, encoded by KCNJ2,
KCNJ12, KCNJ4, and KCNJ14 genes, respectively (215,
282). Four a-subunits (each containing 2 transmem-
brane segments, S1 and S2) combine to form the tetra-
meric, functional Kir channel (FIGURE 3) (217). IK1
channels may also have other, as yet undefined, acces-
sory subunits. Remarkable differences have been
observed between currents flowing through the differ-
ent Kir channel isoforms (63) expressed in mammalian
cell lines (FIGURE 9), thus raising the possibility that dif-
ferent species and cardiac tissue types express different
channel isoforms, with various phenotypes. Further
research will elucidate the exact roles of different Kir
channel isoforms.
IK1 is considered one of the most important currents
securing the resting membrane potential and shaping
terminal repolarization in phase 3 of the action potential
(FIGURE 4). According to classical electrophysiological
principles, one would expect potassium channels to
conduct current more easily in the outward direction, as
the intracellular K1 concentration is much greater than
the extracellular. Instead, inward rectification means that
the steady-state current decreases at potentials positive
to about 50 mV. This inward rectification was attrib-
uted to channel inactivation caused by intracellular
Mg21 and polyamines (284, 285). At potentials more
negative than the K1 reversal potential, IK1 is an inward
current that has a rapidly inactivating component (286)
negative to 120 mV, but the physiological importance
of this inactivation has not been established. This cur-
rent is regularly measured as a Ba21-sensitive steady-
state current at the end of voltage pulses (287).
However, Ba21 is not fully selective for any of the K1
channels described so far, and the steady-state current-
voltage relation measured can also include other, not
well-characterized, currents, described as “leak” or “pla-
teau” currents (Ileak or Ip, respectively) (4, 283, 288).
There are reports suggesting that intracellular [Ca21]
changes can modulate IK1 (287, 289, 290), possibly rele-
vant to frequency-dependent APD regulation or in cer-
tain pathological settings (291). IK1 is also increased by
elevated extracellular K1 concentration ([K1]) (292, 293).
Hyperkalemia increases IK1 by electrostatically destabi-
lizing Mg21- and polyamine-induced IK1 block by displac-
ing these cations from their binding sites (294).
Activation of both the a1/PKC and b1/PKA pathways have
been shown to reduce IK1 in human isolated cardiomyo-
cytes (295, 296). A similar effect of neurokinin-3 was
observed on IK1 in rabbit and human atria (297). These
results further emphasize the importance of autonomic
control of atrial APD and electrical function. IK1 can be inhib-
ited (FIGURE 6) by Ba21 in the micromolar range (140) and
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by the organic compound PA-6 in the nanomolar range
(298).
The autosomal dominant mutation of KCNJ2 causes
Andersen–Tawil syndrome (LQT7), having a characteris-
tic triad of episodic flaccid muscle weakness, ventricular
arrhythmias, and prolonged QT interval (299) (TABLE 1).
Pharmacological approaches to investigate KCNJ2 loss-
of-function mutation revealed that the IK1 blocker BaCl2
prolonged the QT interval without causing a major
increase in transmural depolarization. EADs and sponta-
neous torsades de pointes arrhythmias were not
observed, nor could they be induced by electrical stimu-
lation. These observations may explain why QT prolon-
gation of the Andersen Tawil syndrome was found to
be relatively benign in clinical settings (300).
The upregulation of Kir2.1 was observed in atrial fibril-
lation, where it may contribute to APD shortening (205).
In contrast, Kir2.1 downregulation was reported in HF,
leading to APD prolongation and facilitating delayed
afterdepolarization (DAD) formation (157). Sections 7.1,
7.2, 7.3, and 7.5 provide more detailed information
regarding the relevance of altered IK1 function and
expression in several diseases.
3.6. Ultrarapid Delayed Rectifier Current
The channel carrying the ultrarapid delayed-rectifying
potassium current (IKur) was first cloned from human ven-
tricles (301) but is markedly more expressed in atria
(302). At first, it was considered to be a sustained com-
ponent of Ito (303)—“Ito,sus.” However, this current is car-
ried by a distinct channel consisting of one Kv1.5
a-subunit, encoded by the KCNA5 gene, and Kvb1.2 and
1.3 accessory subunits (304, 305).
IKur is activated rapidly upon depolarization at mem-
brane potentials more positive than 0 mV, with an activa-
tion s of 13 ms at 0 mV potential (302). IKur inactivates
slowly at depolarized potentials, with a double-exponen-
tial s (609 ms and 5,563 ms, respectively, at 140 mV
voltage) (306), and its inactivation can be enhanced by
sympathetic stimulation (307). This current is thought to
operate during phases 1–3 of the action potential of
atrial cardiomyocytes and Purkinje fibers but not in ven-
tricular muscle. However, this was challenged by the
group of Carnes (308), who measured IKur as a 4-AP-sen-
sitive current in dog ventricular myocytes. In these dog
ventricular myocytes, 50 mM 4-AP also lengthened APD.
These findings, however, need to be confirmed by other
investigations. In connection with this, similar mRNA
expression levels were measured in ventricles and in
Purkinje fibers, but one order of magnitude smaller than
in atria (85). Since mRNA measurements from cardiac
samples may be contaminated by coronary vessel neu-
ronal tissue and also mRNA from fibroblasts, whether
1099
 VARRÓ ET AL.
IKur exists and/or operates in ventricular muscle is still
not fully clarified (252). This question is particularly im-
portant because the impact of IKur on the cardiac repola-
rization seems complex (309). After the discovery of IKur,
it was thought that selective IKur inhibitors would have a
particular advantage in the treatment of atrial fibrillation,
by lengthening APD and ERP in the atria but not in the
ventricles. Despite promising animal experiments, these
expectations have not been fulfilled, since clinical stud-
ies did not result in convincing outcomes with newly
developed IKur blockers (FIGURE 6), e.g., XEN-D0101
and XEN-D0103 (310, 311). Inhibition of IKur by XEN-D0101
and XEN-D0103 (310) moderately but significantly
increased APD in atrial preparations from patients with
atrial fibrillation and remodeling, whereas no significant
changes were observed in preparations from patients
with sinus rhythm (309). These experiments also
showed that IKur inhibition shifts the atrial plateau phase
toward the positive direction, thus potentially affecting
activation, inactivation, or deactivation of other plateau
currents, most notably IKr. Thereby, IKur inhibition may
produce variable effects of APD and repolarization
depending on tissue and experimental conditions (154).
This could have important implications if IKur is actually
present in the ventricles, where repolarization reserve
would be decreased by IKur inhibition, with a consequent
increase in proarrhythmic risk. IKur is under adrenergic
control: a1-receptor stimulation reduces and b1-receptor
stimulation increases this current in atrial myocytes (306).
3.7. Calcium-Activated K1 Current
This current is conducted by small-conductance cal-
cium-activated potassium channels (SK2 or KCa2.1–2
and 3), which constitutively bind calmodulin and are
encoded by KCNN1, KCNN2, and KCNN3 genes (5). The
question of whether a calcium-activated K1 current
exists in cardiac tissue and what impact it could have on
the action potential was raised long ago (312). Although
>35 yr have passed since then, and its existence is now
well established in various species and tissues (313), its
physiological and pathophysiological roles in cardiac
muscle are still not fully elucidated. Most evidence sug-
gests that this current plays a role in the atria (5, 314),
and it is also implicated in diseases such as atrial fibrilla-
tion and heart failure (5, 315–317). A recent study in rat
ventricle showed that SK2 channels are upregulated in
HF and also enhanced by PKA phosphorylation (318). In
atrial myocytes isolated from patients with AF, SK2 cur-
rent was increased by enhanced activation of CaMKII
(319). The calcium-activated K1 current is activated in a
voltage-independent manner or in response to intracel-
lular Ca21 concentration increase, with a half-maximal
activation of 300 nM [Ca21]i (320). Despite SK2 channel
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expression, this current was not detected, nor was APD
lengthened by apamin, the most established inhibitor of
this channel, in rat, dog, rabbit, and human undiseased
ventricular muscle, thus bringing into question its role in
physiological conditions (321). However, other studies
have reported an important role for SK2 channels in the
human atria.
Most of the evidence regarding the highly apamin-
sensitive SK2 current originates from experiments
carried out in mice, rats, or rabbits (313, 315, 322,
323). In these species, atrial cellular electrophysiol-
ogy is not well explored and may differ from dogs or
humans. In addition, a marked chloride current was
described in rabbit atria that was not found in dog or
human atria (324). Furthermore, some of the evi-
dence comes from drug studies performed with
NS8593, a putative selective inhibitor of SK2 chan-
nels (5), whose effects on all important ionic currents
in native cardiac cells have not been tested. The-
refore, further investigations are needed for a better
understanding of the exact role of SK2 current in car-
diac physiology and pathophysiology, which is cur-
rently a very interesting and important issue.
3.8. Ligand-Gated Ion Channels
3.8.1. ATP-sensitive potassium channels.
ATP-sensitive potassium channels, carrying the IK,ATP
current, were first identified in cardiac sarcolemmal
membrane by Noma in 1983 (325). KATP channels were
first cloned by Aguilar-Bryan and colleagues (92) and
comprise heterooctamers consisting of four inward-rec-
tifying potassium channel pore-forming subunits (Kir6.1
or Kir6.2, encoded by KCNJ8 and KCNJ11 genes, respec-
tively) and four ATP-binding cassette protein sulfonyl-
urea receptors (SUR1 or SUR2, encoded by ABCC8 and
ABCC9 genes, respectively) (326). The SUR2 has two al-
ternative RNA splice variants, SUR2A and SUR2B; the
two polypeptides differ in their COOH terminals (327).
Different tissues express KATP channels with distinctly
different subunit composition, thus leading to distinct
pharmacological properties of these channels; the myo-
cardial plasma membrane KATP channel consists of
Kir6.2/SUR2A (327). At first glance, their nomenclature
might be misleading: these channels are kept closed by
physiological intracellular ATP levels in normoxic cardiac
tissue, and they activate during metabolic stress, when
the ratio of ATP to ADP is decreased, e.g., in myocardial
ischemia (328). This makes these channels unique,
directly connecting cellular metabolism to membrane
excitability. KATP channels are not regulated by mem-
brane voltage or calcium levels. Indeed, they belong to
the inward rectifier (Kir) potassium channel group, with
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
IK,ATP exhibiting weak inward rectification properties on
the current-voltage relationship that is regulated by in-
tracellular Mg21 and polyamines (329–331). Activation
of sarcolemmal IK,ATP during myocardial ischemia heter-
ogeneously shortens the action potential, and may pro-
mote reentry (31). Accordingly, several investigations
found KATP activation to be proarrhythmic (332), thus
suggesting sarcolemmal IK,ATP inhibition for the preven-
tion of myocardial ischemia and ischemia-reperfusion-
induced arrhythmias (333–335). In contrast, some stud-
ies found no antiarrhythmic effects of KATP blockers in
this setting (336, 337). Furthermore, pharmacological
KATP channel activation was also found to exert antiar-
rhythmic effects (200, 338, 339) that could be, at least in
part, be explained by reduction of monophasic action
potential duration heterogeneity (340) and decreased
triggered activity in Purkinje fibers upon KATP opener
administration after myocardial infarction (341, 342). It
should be also emphasized that KATP channel activation
is very important for prolongation of cell survival during
ischemia, since, according to the classical hypothesis,
the consequent action potential shortening would
reduce contractility by reducing calcium entry into the
cardiomyocytes and enhancing Ca21 extrusion via for-
ward-mode NCX activity (343–345). However, cardio-
protection following sarcolemmal IK,ATP activation in
quiescent myocardial cells subjected to hypoxia was
also observed (346), suggesting that decreased Ca21
overload via reduced reverse-mode NCX activity during
resting membrane hyperpolarization (347) can also con-
tribute to sarcolemmal KATP-mediated cardioprotection.
Therefore, the effects of KATP channel modulation on is-
chemia and ischemia-reperfusion-associated cardiac
arrhythmias remains controversial.
In addition to the KATP channels found in the sarco-
lemma, KATP channels are also present in mitochondria
(348, 349). Evidence suggests that both sarcolemmal
and mitochondrial KATP play cardioprotective roles, albeit
via different mechanisms (350). However, because of the
lack of truly specific modulators for sarcolemmal and mi-
tochondrial KATP channels, this remains controversial and
further research is needed.
3.8.2. Acetylcholine- and adenosine-activated
potassium channels.
It has been known for a long time that acetylcholine short-
ens APD and has been implicated in atrial fibrillation (351).
The ion channel that is directly affected by acetylcholine
is called GIRK1/4 or Kir3.1/Kir3.4 channel (352, 353),
encoded by KCNJ3 and KCNJ5 genes, whose a-subunits
are closely coupled to muscarinic M2- and adenosine A1-
receptor proteins (354). These channels carry an inwardly
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rectifying current, the acetylcholine-activated potassium
current (IK,ACh), and are largely expressed in atrial, SA,
and AV nodal cells (355, 356). IK,ACh (355, 356) is particu-
larly important in atrial, sinus, and AV nodal cells where
they are abundantly expressed. Genes for Kir3.1 and
Kir3.4 are also present in significant amounts in human
cardiac Purkinje fibers (85), consistent with the observa-
tion that acetylcholine and carbachol shorten APD via
IK,ACh in atria, SA, and Purkinje fibers (357). However, its
influence on repolarization in the ventricles is uncertain
(205), and its expression level is relatively low (85). It
must be emphasized that increased parasympathetic
tone and adenosine can also indirectly decrease ICa,L am-
plitude, through the G inhibitory protein decreasing
cAMP, thus contributing to shortening of repolarization
and shifting the plateau potential toward the negative
direction. The IK,ACh-induced repolarization shortening is
generally considered an important factor in the develop-
ment of atrial fibrillation (358), and this initiated intensive
efforts in the drug industry to develop specific IK,ACh inhib-
itors (359). Cholesterol was also reported to enhance
IK,ACh (360). The IK,ACh current has an important role in
modulating the resting or maximal diastolic potential as
well, thus hyperpolarizing atrial, SA, and AV nodal tissues
and Purkinje fibers. This effect interferes with the pace-
maker function, slowing the rate of spontaneous automa-
ticity (361), and it could also slow conduction in the SA
and AV nodes, since hyperpolarization can increase the
potential difference between the maximum diastolic
potential and threshold of activation of ICa,L, which is re-
sponsible for depolarization in these tissues.
It has been reported that IK,ACh is constitutively active
(362) in atrial cells isolated from patients with chronic
atrial fibrillation (358) and therefore plays a pivotal role
in the shortening of APD or ERP and in the development
of atrial fibrillation. Interestingly, however, downregula-
tion of KCNJ3 gene coded mRNA, Kir3.1 channel protein,
and IK,Ach and upregulation of microRNA (miR)-30d were
also observed in atrial tissue obtained from patients with
atrial fibrillation (363). In this study, downregulation of
Kir3.4 protein was also reported (363), thus suggesting a
complex, microRNA-regulated ion channel expression in
atrial fibrillation that needs further investigation. In addi-
tion, after adenosine-induced atrial fibrillation, APD
shortened, more so in the right than in the left atrium,
and this effect was prevented by inhibition of IK,ACh with
the selective blocker tertiapin (364). Accordingly, the
expressions of both adenosine receptor and Kir3.4
GIRK4 channel protein were different between the right
and the left atrium (365), thus suggesting a possible role
of IK,ACh effect heterogeneity in evoking atrial fibrillation.
Recently, it has been reported that an inherited gain-
of-function mutation of KCNJ5 caused familial human
sinus node disease. The enhanced activity of GIRK
1101
 VARRÓ ET AL.
channels was associated with maintained hyperpolariza-
tion of the pacemaker cells that resulted in reduced
heart rate (366).
3.9. Chloride Channels
Chloride or anion currents in cardiac muscle were
described long ago (367). However, despite intensive
and valuable research by some laboratories, relatively
little attention has been paid to their possible role in car-
diac electrophysiology and arrhythmogenesis (368).
One possible explanation is that the functions of chlo-
ride channels are diverse (369, 370) and complex and
their activation usually needs external triggers like
enhanced intracellular cAMP, Ca21, and swelling or
stretch (371). Also the research on Cl currents is
hindered by the lack of specific blockers, since the
established inhibitors of these currents, e.g., DIDS,
9-anthracene (9-AC), tamoxifen, and Cd21, are not
specific. For these reasons, there are uncertainties
regarding the degree to which Cl channels affect dif-
ferent types of cardiac action potentials. In the basal
condition, they carry less current than other well-
established transmembrane ion channels. However,
in pathological conditions they may play a more im-
portant role on arrhythmogenesis than previously
thought. Therefore, Cl channels deserve more atten-
tion, ideally in large-animal or human hearts.
So far, at least four Cl channels have been identified
convincingly in the heart (369, 370).
3.9.1. Calcium-activated Cl channels.
It has been suggested that a current with properties sim-
ilar to Ito may be carried by Ca21-dependent chloride
and potassium currents (372, 373). In this context, it is
important to note that the first report of Ito in calf Purkinje
fiber by Dudel et al. (372) attributed the current to a Cl
conductance. The kinetics of this Ca21-dependent Ito
reflects the kinetics of the calcium transient or rather the
changes of intracellular Ca21 in the vicinity of the sarco-
lemma. This current was also defined earlier as Ito2 or
Ito,slow and could be abolished by depleting the intracel-
lular Ca21 store with caffeine (374) or directly inhibited
by DIDS or SITS (375) or by 9-anthracene (9-AC). To
avoid confusion, it must be emphasized that this current
should be distinguished from the Kv1.4 current, which
has also been referred to recently as slow Ito because of
its slow recovery from inactivation. The physiological
and pathophysiological roles of the Ca21-dependent Ito
are not well defined but were suggested to play some
role in frequency-dependent APD regulation and to
secure or shorten repolarization, possibly preventing or
diminishing calcium overload in pathological settings
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(376). It has been also demonstrated that TMEM16 and
Bestrophin-3 are colocalized with Cav1.2 in canine and
human left ventricular myocytes. In line with this, it was
found that activation of calcium-activated Cl current
(ICl,Ca) requires Ca21 entry through sarcolemmal ICa,L,
and it is activated by Ca21 release from the SR.
Furthermore, ICl,Ca exerts an early repolarizing and a late
depolarizing component during the action potential,
determined by 9-anthracene current in canine ventricu-
lar myocytes (377).
Despite the fact that ICl,Ca had been discovered a
long time ago in the heart, its genetic background was
not known for some time and was first attributed to the
bestrophin channel protein encoded by the VMD gene
(378–380), even if later TMEM16 was reported as an al-
ternative (381–383). The impact of this current on the
action potential is different from the other Cl currents
since it is strongly and dynamically dependent on the in-
tracellular Ca21 concentration (375, 384, 385). It has an
important contribution to phase 1, early plateau repolari-
zation, and it also contributes to the repolarization
reserve. During Ca21 overload, when spontaneous
Ca21 release can happen during diastole, ICl,Ca can con-
tribute to the development of DADs by carrying inward
current at voltages more negative than the Cl equilib-
rium potential (386). Recently, an anoctamin 1 (ANO1)-
encoded Ca21-activated Cl channel was identified in
the ischemic heart, and its increased density was attrib-
uted, at least in part, to the genesis of ischemia-induced
arrhythmias (387).
In contrast, in 5-day infarcted canine heart, the Ito2 cur-
rent measured from myocytes of the epicardial border
zone exerted a significantly smaller peak amplitude,
which may contribute to the development of an abnor-
mal action potential (388).
3.9.2. cAMP-dependent cystic fibrosis
transmembrane conductance regulator Cl
channels.
These channels are mostly closed under basal condi-
tion, and they carry outwardly rectifying Cl current
only when intracellular PKA- and PKC-dependent
phosphorylation is enhanced. Since the equilibrium
potential for Cl in normal conditions is between 65
and 40 mV (389–391), they can carry both inward
and outward current during the action potential.
However, because of its outward rectification, the
main effect of the cystic fibrosis transmembrane con-
ductance regulator (CFTR) Cl current is to shorten
APD and consequently ERP, which in turn may facili-
tate reentry arrhythmias. Interestingly, it was found
that the CFTR Cl current abolishes early and late
preconditioning and also plays a role in
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
postconditioning-related cardioprotection (392). It
was also reported that intracellular Na1 modulated
the cAMP-dependent regulation of this channel (391).
3.9.3. Swelling- and acidosis-activated CIC-2 Cl
channels.
In cardiac myocytes, another Cl channel was also
described, encoded by the CIC-2 gene and carrying a
current that is activated by hyperpolarization more nega-
tive than 40 mV, with a relatively slow biexponential
time course (393). The current is increased by swelling
and acidosis, and it is blocked by 9-AC and Ca21 but not
by tamoxifen or DIDS (394). CIC-2 current, also called
ICl,ir, is strongly rectifying in the inward direction (370,
394, 395), and therefore it plays no or little role in car-
diac repolarization. However, it seems to be important in
the SA node (396), where it is abundantly expressed,
and may contribute to enhanced automaticity during is-
chemic cell swelling and acidosis.
There are some data regarding a strongly outwardly
rectifying acidosis-induced Cl current (ICl,acid), but its
molecular entity is unknown. It can be assumed that this
current can contribute to the APD shortening in ischemia
(397).
Protein tyrosine kinase is one of the initial factors
responding to cell swelling, providing the possibility that
tyrosine kinase is an important upstream regulator of the
swelling-activated Cl current (ICl,swell) (398, 399).
Furthermore, angiotensin II is released during stretch,
and it is implicated in cardiac remodeling and develop-
ment of HF, where ICl,swell is chronically activated (400,
401). Block of AT1 receptors prevented activation of
ICl,swell, thus suggesting a potential role of angiotensin II
in the activation of the current (402).
3.9.4. Volume-regulated CIC-3 Cl channels.
The channel encoded by the CIC-3 gene carries a time-
independent and robust outwardly rectifying Cl current
(ICl,swell) that is small in basal isotonic conditions but is
increased by swelling or stretching (369, 370). During is-
chemia and reperfusion, when swelling of myocytes can
occur, ICl,swell shortens APD and may enhance disper-
sion of repolarization between ischemic and nonische-
mic zones, thus facilitating both atrial and ventricular
fibrillation (371, 393). Since the CIC-3 channels are
expressed in atria, ventricles, Purkinje fibers, and SA
node cells, they could also play a role in mechanotrans-
duction and in normal pacemaker function, and they
may contribute to the development of extrasystoles by
promoting membrane depolarization in both the atria
and ventricles during stretch (403, 404). CIC-3 chloride
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channels are constitutively active in cardiac hypertrophy
and heart failure (370, 371). This may limit APD prolonga-
tion, but it may facilitate DADs at elevated diastolic
[Ca21]. In addition, since Ito and IK1 are downregulated in
the failing heart (7), this persistent ICl,swell may further
change the balance of inward and outward currents to-
ward the inward direction, thus favoring membrane
depolarization (405). It was also reported that targeted
inactivation of the CIC-3 gene prevents the cardiopro-
tective effect of the late but not the early phase of pre-
conditioning in mice (405).
3.10. Two-Pore Domain Channels
Two-pore domain K1 channels (K2P) are widely exp-
ressed in different organs, including the heart, but rela-
tively little is known regarding their function in the myo-
cardium. Except for a few studies, the physiology of
these channels has been studied only in mice or rats,
but they are abundantly expressed in the human heart
as well (406, 407). In general, two-pore domain K1 chan-
nels represent a superfamily of large-conductance K1
channels, which lack voltage dependence or may ex-
hibit outward rectification (64, 408). They are composed
of two a-subunits, each containing four transmembrane
segments that form two ion-conducting large-conduct-
ance pores (FIGURE 3), and may be associated with sev-
eral types of accessory subunits (5, 64). These channels
are considered important determinants of background
K1 conductance (408). They contribute to the resting or
maximal diastolic potential and to the repolarization
phase and are regulated by stretch, pH, temperature,
and lipids or various signaling messengers (408). In gen-
eral, the exact roles of the two-pore channels in cardiac
electrophysiology and arrhythmogenesis are not well
explored and offer challenging targets for further res-
earch. Therefore, future intensive research seems
worthwhile to clarify the function of these channels in
larger mammals and humans, including their potential
role in arrhythmogenesis.
3.10.1. TWIK-1 channels.
The “two-pore” or “Tandem of pore domains in a
weak inward-rectifying K1 channel 1” (TWIK-1) channel,
encoded by the KCNK1 gene, was first described in
1996 (407). They are expressed in the heart, are acti-
vated by mechanical stretch, intracellular acidification
(409), and polyunsaturated fatty acids, and facilitate
repolarization and membrane hyperpolarization (5).
Recently, it has been reported that TWIK-1 channels
can change selectivity from K1 to Na1 under extrac-
ellular acidic conditions and low K1 concentration
1103
 VARRÓ ET AL.
(410), and this phenomenon is responsible for the
paradoxical depolarization contributing to enhanced
arrhythmic activity in hypokalemia (411).
3.10.2. TASK-1 (K2P3.1) and TASK-3 (K2P9)
channels.
The “TWIK-related acid-sensitive K1” (TASK) channels,
encoded by the KCNK3 and KCNK9 genes, respectively,
are voltage-independent channels highly sensitive to
extracellular pH, and TASK-1 channels can be selectively
inhibited by A293 (5, 64, 412). TASK-1 channels can con-
tribute to APD shortening in ischemia because of their
inhibition by extracellular acidosis (412). In addition, they
were shown to be upregulated in the atria of patients
with chronic atrial fibrillation and preserved cardiac func-
tion (413), whereas a downregulation was recently
observed in the atria of patients with atrial fibrillation and
reduced cardiac function (414, 415), associated with atrial
APD shortening (412) and prolongation, respectively. In
human atria, TASK-1 channels can form heterodimers
with TASK-3 channels (KCNK9) that can be regulated by
stress and thus contribute to the pathogenesis of
chronic atrial fibrillation (416, 417). Interestingly, a gain-
of-function mutation in the TASK-4 (KCNK17) channel,
which is sensitive to pH in the alkaline direction, was
reported recently (418), linked to a severe conduction
disorder and suggesting the role of the TASK-4 channel
in both repolarization and membrane hyperpolarization-
related conduction changes.
A AP prolongation
B C
Human &
Large mammal
Ventricle
ICa reactivation
0 mV
Phase-2 Phase-3
EAD EAD
INCX augmentation
Spontaneous
Ca2+ release
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3.10.3. TREK-1 (K2P2.1) channels.
The “TWIK-related K1-channel” (TREK-1) represents
another two-pore K1 channel entity that is widely and
abundantly expressed in various cardiac tissues (5, 419,
420). TREK-1 channels are particularly important since
they carry the outwardly rectifying K1 current activated
by stretch (420), the so-called stretch-activated cation
current (SAC), temperature, or polyunsaturated fatty
acids, the latter also called arachidonic acid-sensitive
current (IKAA). TREK-1-mediated SAC can shorten repola-
rization, by carrying outward current during the whole
duration of the action potential, and hyperpolarize the
membrane, thus in turn affecting spontaneous fre-
quency and impulse conduction. This current seems to
play a larger role in the atria and SA node than in the
ventricles. However, a pathophysiological effect known
as “commotio cordis,” describing the accidental chest
hit that can cause sudden cardiac death, is presumably
due to the function of TREK-1 channels in the ventricles
(420). Interestingly, mutations in the selectivity filter can
make the TREK-1 channels permeable to Na1, thus caus-
ing ventricular tachycardia (421). TREK-1 channels are
downregulated in atrial fibrillation and heart failure
(422–425). They also mediate cardiac fibrosis and dia-
stolic dysfunction, via activation of c-Jun NH2-terminal ki-
nase (JNK) in myocytes and fibroblasts (426, 427), thus
enhancing the propensity of arrhythmias. Genes (Popdc
1–3) were identified encoding the cAMP-binding Popeye
protein, which associates with TREK-1 channels,
FIGURE 10. Mechanisms of afterdepolari-
zation formation in cardiomyocytes. In ven-
tricular myocytes from large mammals,
phase 2 early afterdepolarizations (EADs)
DAD
are associated with L-type Ca21 current (ICa,
) recovery from inactivation and reactivation
L
during prolonged action potentials (APs) (A).
Spontaneous sarcoplasmic reticulum Ca21
release, which increases Ca21 extrusion via
Na1/Ca21 exchange (inward current) (INCX),
can lead to phase 3 EADs (B) or delayed
afterdepolarizations (DADs) (C) when occur-
ring during or after the termination of repola-
rization, respectively. (Reproduced from Ref.
434 with permission.)
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
modifying their function. Accordingly, the absence of
Popdc 1–2 genes should reduce TREK-1 current, increas-
ing sinus node activity; however, the opposite has been
observed experimentally in mouse mutants (242, 428),
suggesting the presence of yet unidentified interaction
partners for Popeye proteins. Recently, it was proposed
that TREK-1 channels could also play a role in establish-
ing the two levels of resting potential (429), a phenom-
enon that had been described long ago in ventricular
and Purkinje fibers (430, 431).
3.10.4. Two levels of resting potential.
Because of the N-shaped steady-state current-voltage
relationship of the Purkinje (431, 432) and ventricular
(433) cells, two stable levels of resting membrane poten-
tials can develop in these cells. The conductance of po-
tassium channels at 4 mM extracellular [K1] near the
equilibrium potential for K1 is 100 times greater than
that of the Na1 and Ca21 background channels; there-
fore it determines the resting potential to be around
90 mV. When the conductance of potassium channels
decreases because of IK1 inward rectification (FIGURE 9)
and/or hypokalemia, the conductance ratio of K1 and
Na1/Ca21 channels can dramatically decrease, which
results in a second stable, albeit lower, potential in the
range of 50 to 25 mV depending on extracellular
[K1] or the actual strength of the background Na1 and
Ca21 currents (431–433). This second stable potential
has an important role in the genesis of the arrhythmo-
genic triggered spontaneous automaticity like phase 2
or 3 early afterdepolarizations (FIGURE 10).
3.11. Transmembrane Ion Transporters
Transmembrane ion transporters, which exchange cati-
ons across the sarcolemma, are essential to maintain
the uneven ion distribution between the extra- and intra-
cellular space. These ion pumps influence cardiac cellu-
lar electrophysiology indirectly, by changing various
intracellular concentrations (282), most importantly
Ca21, which activates and regulates several other trans-
membrane ionic currents. In addition, some transmem-
brane ion transporters are electrogenic, i.e., they
exchange charges unevenly, thereby carrying inward or
outward transmembrane ion currents, which can influ-
ence the action potential repolarization and maximal dia-
stolic or resting potential.
3.11.1. The Na1-K1 ATPase/pump.
The primary role of the Na1-K1 pump (NKA) is to
remove from the intracellular space the Na1 that
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enters during the action potential (36). The pump
exchanges 3 Na1 for 2 K1 and thereby carries an out-
ward current (INa/Kpump) (282). The size of the gener-
ated current ranges between 0.34 and 0.68 pA/pF
(37), which can result in RMP changes of 8–9 mV at
near-physiological conditions (35, 38), even though
its effect is often overlooked. It plays an important
role in ionic homeostasis and also in cardiac repolari-
zation (435). The INa/Kpump shortens repolarization in
simulations (436), contributes to the resting potential,
and, if its activity is enhanced by elevated extracellu-
lar [K1], intracellular Na1 concentration ([Na1]),
cAMP, or high firing rate (437), can even hyperpolar-
ize the cell (438). The Na1-K1 pump needs energy to
work, since it pumps out Na1 against its electrochem-
ical gradient. The source of this energy comes from
intracellular ATP, through the function of the Na1-K1-
ATPase, which is part of the pump (438). So far, two
a-subunits have been identified for NKA: a1 and a2
(439, 440). The a1 is evenly distributed in the sarco-
lemma (441), and it regulates intracellular Na1 in the
bulk of the cytoplasm. The a2 is mostly expressed in
the dyadic cleft (440, 442, 443) and therefore may
have a special role in controlling, via interaction with
the NCX, the Ca21 released from the sarcoplasmic
reticulum (440). The fact that the a1-subunits of the
Na1-K1 pump are evenly distributed in the sarco-
lemma and carry >80% of the INa/Kpump (440, 444)
raises the possibility to develop drugs that selec-
tively modulate the Na1-K1 pump a1- and a2-subunits
(440). As well as being regulated by intracellular Na1
concentration (445), Na1-K1 pump activity is con-
trolled by the phosphorylation of FXYD protein phos-
pholemman (PLM) (446). Dephosphorylated PLM
exerts a tonic inhibition of Na1-K1 pump, and its
phosphorylation would relieve this inhibition. Sti-
mulation of the b-receptor increased the pump activ-
ity (447), and a-receptor activation enhanced the
Na1-K1 pump in canine Purkinje fibers (448). It was
further reported that insulin flattened the pump cur-
rent (Ip)-voltage (V) curve of the pump, depending on
the patch pipette [Na1] and voltage (449).
The b-subunit is also essential for pump function, provid-
ing a stabilization role for the a-subunit. The c-subunit
seems to contribute in regulation of the sodium pump
activity (450, 451).
The cardiac glycosides (such as ouabain) are specific
inhibitors of the Na1-K1 pump (452). Application of 1 μM
ouabain increases the AP duration at 90% repolarization
(APD90) by 17% and 10 μM by 21%, also increasing the AP
plateau (453).
The Na1-K1 pump is a key player in the cellular mech-
anism of ischemia-reperfusion injury. In myocardial is-
chemia, reduced ATP levels cause a decline in activity
1105
 VARRÓ ET AL.
for the Na1-K1 pump. The suppressed function of the
pump leads to elevated intracellular Na1 level, which
activates reverse mode of the Na1/Ca21 exchanger
(NCX), thus providing enhanced Ca21 entry and Ca21
overload (4).
3.11.2. The Na1/Ca21 exchanger.
The NCX is a member of a large Ca21/cation antiporter
superfamily (454). The mammalian tissues express three
NCX isoforms, NCX1–NCX3, encoded by the genes
SLC8A1 SLC8A3, respectively (455–457). Alternative
splicing of the primary nuclear SLC8A1 transcript gener-
ates at least 17 NCX1 proteins (454), and the NCX1.1
splice variant represents the cardiac isoform of the NCX
(458). The NCX1.1 comprises 10 transmembrane seg-
ments, where two groups of five transmembrane seg-
ments are separated by an intracellular loop (459). This
loop contains the exchanger inhibitory peptide (XIP)
region that plays a key role in NCX inactivation by
increased intracellular [Na1] (460, 461). The cytoplasmic
loop also contains two calcium-binding domains that are
responsible for Ca21 regulation of the NCX (462). The
main function of the NCX is to control calcium flux
through the plasma membrane, and it transports 3 Na1
for 1 Ca21, using the driving force of the Na1 gradient
provided by the NKA as discussed previously (458,
463–465). The stoichiometry makes NCX electrogenic
(466), with one net positive charge moving either into
the cell (“forward mode) or out of the cell (“reverse
mode”), eliciting inward or outward transmembrane cur-
rent (INCX), accordingly. The magnitude and direction of
ion transport and generated transmembrane current
therefore depend on the membrane potential as well as
the transmembrane concentration gradients of Na1 and
Ca21, thereby dynamically changing during the action
potential (467). During the early phases of the action
potential when transmembrane voltage is positive and
intracellular Ca21 is low, Ca21 enters the cell by reverse
NCX, generating outward current. Later on, when [Ca21]i
is increased, Na1 enters and Ca21 leaves the cell, gen-
erating an inward current (468). This function results in
complex changes on the cardiac action potential (467)
and arrhythmogenicity depending on heart rate, possi-
ble Ca21 overload, or NCX expression levels. It was
reported that a substantial degree of selective NCX inhi-
bition did not change the shape of the action potential
waveform in normal physiological settings in dog ven-
tricular papillary muscle (469, 470) and in human right
atrial preparations (471). However, when NCX forward
mode was experimentally enhanced in dogs, selective
NCX inhibition by 1 mM ORM-10962 shifted the plateau
voltage toward negative values (469). On the contrary,
when reverse NCX mode was experimentally
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augmented, 1 mM ORM-10962 moderately lengthened
the action potential (469). It is generally considered that
NCX is the major, but not the only (472, 473), source of
Ca21 removal from the cell during the later phase of the
action potential and diastole, carrying an inward current
that can contribute to both EADs and DADs (FIGURE
10). Indeed, it was demonstrated that inhibition of NCX
abolishes both EAD and DAD development (470, 474–
476) and also arrhythmias caused by enhanced disper-
sion of repolarization (477) or by ouabain application
(469).
Some studies suggest that NCX proteins are rela-
tively concentrated in the dyadic clefts, where the
SR-ryanodine Ca21 release site faces the sarco-
lemma (478–480), but another study (481) provided
different results, and thus this issue is still unresolved
(440, 463). Na1 entering the cell can increase the in-
tracellular Na1 concentration in the small volume of
the dyadic clefts, thereby increasing Ca21 entry into
the cell on reverse-mode NCX (470, 482). This may
increase Ca21-induced Ca21 release from the SR. It
is important to note that Ca21 concentration changes
in the clefts and close to the sarcolemma can be
orders of magnitude higher than in the bulk of the
cytosol (483), which is what is measured routinely
with fluorescent Ca21 indicators. Therefore, experi-
ments can severely underestimate the electrophysio-
logical role of NCX in cardiac myocytes. Further
methodological improvements are necessary to
determine Ca21 concentrations most accurately in
the dyads and clefts in order to better define and
understand the electrophysiological role of NCX in
arrhythmogenesis.
Sorcin is a penta EF-hand protein that interacts with in-
tracellular target proteins after Ca21 binding. It has been
reported that NCX1 could be an important target of sor-
cin: downregulation of sorcin decreases NCX activity,
but a higher level of sorcin increases it (484). It was also
described that insulin is able to increase the NCX activity
via interaction with the 562–670 f-loop domain (485).
Furthermore, the wild-type NCX1.1 associates with the F-
actin cytoskeleton, probably through interactions involv-
ing the central hydrophilic domain of the NCX, and this
association interferes with allosteric Ca21 activation
(486). Phosphatidylinositol 4,5-bisphosphate (PIP2) plays
an essential role in NCX regulation, since PIP2 increases
reverse-mode NCX1 activity, causing a net increase in
Ca21 influx (1133, 1134). Long-chain acyl-CoA esters,
found to be elevated in cardiac ischemia (487), hypertro-
phy (488), and failure (489), have been shown to be en-
dogenous activators of reverse-mode NCX activity by
interacting directly with the XIP sequence, and thus link-
ing altered fat metabolism to NCX function and NCX-
mediated calcium overload in the myocardium, in
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS

pathological conditions (490). Importantly, protons are
powerful inhibitors of NCX1.1 forward-mode activity, fur-
ther emphasizing the role of NCX1.1 as a key contributor
to pathologically altered Ca21 homeostasis and arrhyth-
mia generation during cardiac intracellular acidosis,
including myocardial ischemia (491, 492).
The effects of genetic mutations influencing NCX
function are poorly understood. However, a genetic
mutation in NCX1 was demonstrated to cause cardiac fi-
brillation in a zebrafish model (493).
3.11.3. The Na1/H1 exchanger.
(507) and cell volume (508). The function of NHE is
electrically neutral; therefore, it does not directly
affect the AP and arrhythmogenesis in normal condi-
tions. However, it has been shown to play important
pathophysiological roles by indirectly changing in-
tracellular Na1 concentration and pH (509, 510),
both affecting several ion channels and transport-
ers. The role of NHE is considered significant in
arrhythmogenesis in pathological settings, including
myocardial ischemia-reperfusion, heart failure, or di-
abetes, when intracellular pH or Na1 deviates from
physiological levels (496, 511–514).

The Na 1/H1 exchanger (NHE) was first described in

rat intestinal and kidney tissue (494). Since then,
nine NHE isoforms have been identified (NHE1 to
NHE9, encoded by the genes SLC9A1 to SLC9A9,
respectively) (495, 496), and in the plasma mem-
brane of mammalian myocardial cells NHE1 is the
primary isoform (497). The NHE1 consists of 12 trans-
membrane segments, with the NH2 terminal (500
residues) catalyzing ion transport and interacting
with pharmacological NHE inhibitors and the COOH
terminal (300 residues) responsible for regulation
of the exchanger by calmodulin, PIP 2, and calci-
neurin B homologous proteins (498–504). The NHE1
can be found as a homodimer in the plasma mem-
brane (505). The NHE1 dimer exchanges 2 extracel-
lular Na1 for 2 intracellular H1 in one cycle (506),
and it is an important regulator of intracellular pH
4. TISSUE-SPECIFIC ACTION POTENTIALS
4.1. Sinoatrial Node and Pacemaker Function
The sinoatrial node (SAN) is located in the upper part
of the right atrium, and it has a special role in the
heart, serving as the natural pacemaker. SAN cells
have a relatively low maximal diastolic potential (less
than 60 mV), that, after the termination of repolari-
zation, gradually becomes less negative during the
so-called spontaneous diastolic depolarization—until
it reaches the potential range of L-type Ca21 channel
activation, thereby generating a new action potential.
The exact nature of the pacemaker function in the
SAN is still under debate (515–519). Originally, it was
thought that the slow diastolic depolarization was

0
3
20 mV MDP
4
DD
200 ms

ICaT ICaL ICI

IKr IK(ACh) If INCX Membrane-clock

Ca2+ Cl– K+ K+ Na+ 3 Na+ Ca2+ 2 K+ 3 Na+

Spontaneous,
rhythmic Ca2+ Ca2+ -clock
releases

FIGURE 11. Hypothetical mechanism for sinus node pacemaking. The figure illustrates a typical sinus node action potential (red trace) and the timing
of the membrane and Ca21 clock components. Upon phase 0, the T (ICa,T)- and L(ICa,L)-type Ca21 channels (and presumably the Cl channels, ICl) open,
providing inward current (downward arrows), and depolarize the membrane. During repolarization (phase 3) the opening of the delayed rectifier (I )
Kr
and the acetylcholine-dependent (IK,ACh) K1 currents (upward arrows) repolarizes the membrane to reach the maximal diastolic potential (MDP). Upon
diastolic depolarization (DD), the cAMP-dependent “funny current” (I ) slowly depolarizes the membrane in close cooperation with the sodium-calcium
f
exchanger (I ) that is governed by spontaneous, rhythmic Ca21 oscillations from the sarcoplasmic reticulum.
NCX

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 VARRÓ ET AL.
due to a hyperpolarization-activated inward current.
This current was first described in cardiac Purkinje
fibers and was thought to be carried by Na1, based
on its dependence on extracellular [Na1] (520). Later
on, other studies suggested that the slow diastolic
depolarization was the result of a decaying K1 cur-
rent called IK2 (521, 522). These data were subse-
quently reinterpreted in terms of ionic currents
resulting from extracellular accumulation of K1, and a
hyperpolarization-activated inward current, called
“funny current” (If), carried by both Na1 and K1, was
described by Di Francesco (524) and others (523,
525). Despite the fact that other currents, such as IKr,
T-type ICa and NCX, were also suggested to play a
role in the SAN pacemaker activity (526–529), for
more than two decades since its discovery the major
mechanism underlying the pacemaker function was
generally considered to be If. However, in an early
study of Noma, Morad, and Irisawa (530), the signifi-
cance of If in the SAN pacemaker function was ques-
tioned. These authors showed that cesium, an
inhibitor of If, did not influence the SAN spontaneous
frequency and did not eliminate the epinephrine-
induced increase in SAN frequency. The dominant
role of If in SAN pacemaker function was later also
challenged by studies showing that a cycling sponta-
neous release of Ca21 happens during diastole, and
this can cause spontaneous depolarization by acti-
vating forward NCX as an alternative mechanism for
the pacemaker function (“calcium clock hypothesis”)
(203, 531–534). This controversy seems to be settled
by the “coupled clock hypothesis” (FIGURE 11), sug-
gesting an important role for both the “calcium clock”
and the “membrane clock” (If) (528, 535). Also, in a
recent study, Morad and Zhang (517) demonstrated
and pointed out that If was very small and very slowly
activating at the range of maximal diastolic potential
of the SAN cells ( 60 mV), therefore not enough to
generate a significant amount of pacemaker current.
These authors suggested that expression and func-
tion of inward If in SAN cells can counterbalance the
electrotonic interaction of the more negative resting
potential of the surrounding atrial cells. According to
this suggested function, If is important since it insu-
lates SAN cells from the hyperpolarizing influence of
the atria, thus allowing a proper SAN function.
Consistent with this speculation, Boyett et al. (536)
found higher HCN (If) expression in peripheral rabbit
SAN tissue than in the central core.
A recent study in human induced pluripotent stem cell
(HiPSC)-derived myocytes suggested that mitochondria
could also play a role in the spontaneous activity, setting
the rhythm of the “calcium clock” by taking up and releas-
ing Ca21 from and to the cytosol (517). However, other
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studies suggested that mitochondrial Ca21 transient decay
is slow, and that their Ca21 efflux is relatively small during
one cardiac cycle (463), thus raising questions about a sig-
nificant role of mitochondrial Ca21 release on SAN fre-
quency. Further studies in adult SAN cells are necessary to
confirm the possible role of mitochondria in pacemaking.
In general, SAN frequency can be slowed down by in-
hibiting If, NCX, ICa,L, or IKr in feline, rabbit, and porcine
SAN myocytes (537–540). Inhibition of If and NCX
decreases the slope of diastolic depolarization, while in-
hibition of ICa,L would shift the threshold potential toward
more positive values, and thereby the cycle length is
increased in all cases. Inhibiting IKr prolongs repolariza-
tion of SAN cells and lengthens their spontaneous cycle
lengths. It has to be considered, however, that loss-of-
function mutation of If results in sinus bradycardia, argu-
ing for some role of If in SAN pacemaking (541).
SAN frequency can also be affected by intracellular
cAMP levels. Elevation of intracellular cAMP increases If
and shifts its activation to more negative potentials
(542), which in turn enhances ICa and intracellular Ca21,
further favoring the increase of SAN frequency. Vagal
stimulation has an opposite effect on intracellular cAMP
and SAN frequency. Data from SAN cells isolated from
Girk4 (Kir3.4)-knockout mice lacking IK,ACh suggest that it
may also activate IK,ACh, which can cause hyperpolariza-
tion and may also contribute to SAN bradycardia (543).
SAN cells lack cardiac type Nav1.5 fast Na1 channels,
and therefore their depolarization is caused by ICa,L
(544). Recently, neuronal Nav1.6 Na1 channels were
reported in SAN cells (90, 545), but their role in SAN
function is not well understood (529). The SAN action
potential does not show a distinct plateau phase with
relatively weak IK1 current.
Experimental evidence obtained in spontaneously
beating guinea pig sinoatrial cells suggests that If function
decreases SAN frequency variability, which is the intrinsic
behavior of the calcium clock function (546).
Elucidating the exact mechanisms underlying pace-
maker function and its regulation still remains an impor-
tant task for the future, since it provides the regular
heartbeat but it can also act as a possible trigger for seri-
ous atrial and ventricular arrhythmias (547, 548).
4.2. Atrial Action Potential
Large species-dependent variations make it difficult to
describe the general shape of cardiac action potentials,
including atrial action potentials (FIGURE 12 and
FIGURE 13). There is also significant diversity within the
same heart (549), at least in humans (3, 550), and this
results in a relatively large dispersion of repolarization,
which favors the development of atrial fibrillation.
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS

FIGURE 12. Species-dependent differences in atrial (A) and ventricular (B) action potential configuration. Original action potential recordings at 1 Hz
stimulating frequency from human, dog, rabbit, guinea pig, and rat ventricular muscle preparations recorded by the conventional microelectrode tech-
nique. Unpublished data from our laboratory at the Department of Pharmacology and Pharmacotherapy, University of Szeged.

In most species, the atrial action potential lacks a long
and stable plateau phase. In human atria, most of the
atrial action potential recordings show a plateau phase,
but at a more negative voltage range ( 10 to 30 mV)
than observed in the ventricle. This is due to the function
of the abundantly expressed Ito and IKur potassium cur-
rents (FIGURE 6). Ito in the atria has slower inactivation
kinetics than in the ventricles, having a robust slowly
deactivating component (s = 91 ms at 20 mV), with
slower recovery (551) from inactivation (s = 125 ms) than
the ventricular one. Therefore, frequency-dependent
changes of APD and restitution are different in atrium
and ventricle. In the atria IKur is large (85) and contributes
to repolarization, in contrast with the ventricle, where it
is absent or very weakly expressed (85). Therefore, IKur
inhibition would be expected to prolong the AP.
However, inhibition of IKur shortens repolarization by
shifting the plateau voltage to the positive voltage range
(309), thus changing the activation and deactivation/
inactivation of other plateau currents, such as IKr, IKs, ICa,
and INaLate. IKur inhibition has also been shown to slightly
prolong human atrial APD in tissue obtained from
chronic AF patients (309, 552). However, in this case,
phase 1 and 2 repolarization were delayed and shifted
to positive potentials, because of electrophysiological
remodeling, thus allowing for a larger IKur contribution
compared with normal conditions. It is interesting that, in
rabbit (unlike in human) atrial muscle, sustained Cl cur-
rent was reported after Ito inactivation (324, 553). This
should be taken into consideration when drugs are stud-
ied in rabbit atrial preparations, and it highlights the im-
portance of species-dependent electrophysiological
differences. A distinct, cellular swelling-induced Cl cur-
rent has also been described in human atrial myocytes
(554), which is also modulated by PKA-independent,
cAMP-mediated b-adrenoceptor signaling (555). The ex-
istence and potential role of Nav1.8 channels in INaLate in
the atria represents an interesting issue; however, it is
still the subject of debate (556) and requires further
studies. L-type and T-type ICa have similar properties in
atria and ventricle (557). IK1 current density is relatively
small in the atria, especially in the voltage range
between 80 and 0 mV. This is consistent with the find-
ing of lower Kir2.1 mRNA expression in right atrial com-
pared with right ventricular human tissues (85). Recently,
it has also been reported that neurokinin-3 receptor acti-
vation induced prolongation of atrial refractoriness,
which was attributed to the inhibition of a nonspecific K1
background current (297). It is difficult to measure IKr
and IKs in atrial myocytes, most likely because of the cell
isolation techniques (252). Regardless of that, IKr block
significantly lengthens atrial repolarization, in both

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 VARRÓ ET AL.

FIGURE 13. Distinctly different effects of slow component of delayed rectifier potassium current (I ), transient outward current (I ), and ultrarapid
Ks to
component of delayed rectifier potassium current (IKur) inhibition on ventricular repolarization in human (top) and rat (bottom). In these experiments,
action potentials were recorded in ventricular papillary muscle with the conventional microelectrode technique at 1 Hz stimulation frequency. Note the
extended timescale of the recordings in rat papillary muscle. A: rapid component of delayed rectifier potassium current (IKr) inhibition by 50 nM dofeti-
lide markedly prolonged action potential duration (APD) in human but not rat papillary muscle. B: I block by 100 mM chromanol 293B in human elimi-
to
nated the notch and elevated the plateau potential to positive direction without changing the APD; however, the APD was significantly prolonged in
rat. Since chromanol 293B fully blocks IKs in addition to inhibition of Ito at 100 mM, prior IKs block was elicited by 500 nM HMR-1556 to dissect these
effects (140). C: I inhibition by 3 mM XEN-D0101 (310) does not affect APD in human but markedly prolongs APD in rat ventricular papillary muscle
Kur
(unpublished experiments from the Department of Pharmacology and Pharmacotherapy, University of Szeged).

animal and human studies (558, 559). On the other
hand, the role of IKs in atria is not well explored.
Experiments with chromanol 293B on atrial action
potential are not conclusive, since this drug inhibits both
IKs and Ito (560). It must be emphasized that, in physio-
logical conditions, the atrial plateau voltage is more neg-
ative than the activation threshold of IKs. Therefore, IKs is
not expected to contribute to atrial repolarization.
However, it has been reported that in atrial tissue LQT1,
MinK, and MiRP levels are similar to those in ventricular
tissues (85). On the basis of these results, it can be
speculated that, at fast heart rate (enhanced sympa-
thetic tone) and in situations where the atrial plateau is
shifted to positive voltage, IKs may have a role in atrial
repolarization. Therefore, its modulation could influence
arrhythmogenesis. Indeed, it has been shown that two
gain-of-function mutations in KCNQ1 (S140G and V141M),
detected in patients with AF (275, 277), markedly slowed
deactivation of IKs and contributed to the development
of AF (561). Unlike in the ventricles, most studies showed
the existence and function of small-conductance, apa-
min-sensitive and calcium-dependent potassium current
(SK2) in normal atria, but its significance seems to be far
more pronounced in diseased tissue (5, 314, 316, 317,
562). The increased apamin-sensitive SK current was
found along with decreased mRNA and protein levels of
SK1, SK2, and SK3 channels in human atrial cardiomyo-
cytes isolated from patients with AF (319). However, in the
same experiments CaMKII was increased and its inhibi-
tion by KN-93 reduced the apamin-sensitive SK currents
to a higher degree in myocytes isolated from patients
with AF compared with those in sinus rhythm (319), sug-
gesting that SK channels are more sensitive to Ca21 in
AF patients and CaMKII modulation may represent a
pharmacological target in the management of AF.
Neurohor-monal modulation of the atria is particularly im-
portant. Acetylcholine (358, 563), catecholamines (555,
563), substance P (297), adenosine (564, 565), and sero-
tonin (566) have been reported to influence atrial action
potential and its underlying currents. In the atria, IK,ACh is
robust and even has a small but persistent constitutively
active component, which operates without parasympa-
thetic stimulation and seems greatly augmented during
chronic AF (358). Accordingly, atrial tissue expresses
mRNAs for Kir3.1 and GIRK channels abundantly. Of note,
TWIK TASK channels are also relatively abundantly
expressed in the atria (85), but their roles in atrial electro-
physiology are not well explored yet.

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 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS

A left atrium pulmonary vein smooth muscle

Membrane Potential

Membrane Potential

Membrane Potential
50 50 50
25 25 25
0 0 0

(mV)

(mV)

(mV)
-25 -25 -25
-50 -50 -50
-75 -75 -75
-100 -100 -100

0 1000 2000 3000 4000 0 1000 2000 3000 4000 0 1000 2000 3000 4000

Time (ms) Time (ms) Time (ms)

B control
before stretch 30s after stretch

-50

1s 1s

gadolinium
before stretch 30s after stretch

-50

1s 1s

C
0.25 s

mV

-50

FIGURE 14. Properties of action potentials from left atrial and pulmonary vein myocytes. A: recordings of action potentials from the left atrium and pulmonary
vein and a transmembrane potential in the smooth muscle cell layer. (Reproduced from Ref. 576 with permission.) B: effects of mechanical stretch on the sponta-
neous electrical activity of the pulmonary vein myocardium. Expanded traces obtained before (left) and 30 s after (right) the application of mechanical stretch
(100 mg) in the absence (top) and presence (bottom) of gadolinium. (Reproduced from Ref. 577 with permission.) C: spontaneous action potential with early after-
depolarizations in canine pulmonary veins from dogs subjected to chronic atrial tachypacing. (Reproduced from Ref. 578 with permission.)

4.3. Pulmonary Veins (571, 572), to understand their role (573, 574), the mech-
anisms, and possible treatment of arrhythmias initiated
The spontaneous activity of the pulmonary vein (PV) was and maintained by the PVs. It was demonstrated that tis-
described long ago by several investigators (567, 568). sue with myocardial origin is present in the PVs of dogs
Later, Haïssaguerre and colleagues (569, 570) demon- and guinea pigs, with electrophysiological properties
strated that electrical activity in the pulmonary vein that are similar to but also distinct from the neighboring
sleeves (PVs) in patients has an important role in atrial fi- atrial tissue (568, 575) (FIGURE 14). PVs cells have less
brillation. In the following years, intensive research was negative resting potential and shorter APD than atrial
carried out both in the clinical and experimental fields myocytes and also lack a prominent plateau phase

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 VARRÓ ET AL.
(FIGURE 14). Work on canine PVs found that these cells
either do not show spontaneous diastolic depolarization
or, if they do, their rate is normally lower than that of
SAN cells (576, 579). Stretch can also increase automa-
ticity and induce high-frequency firing in guinea pig PV
cells (577) (FIGURE 14). Sympathetic stimulation or dis-
eases like hyperthyroidism (580) increase intracellular
[Ca21], causing PVs cells to develop triggered activity
(FIGURE 14), and both early (EAD) and delayed (DAD)
afterdepolarizations can occur (578) (FIGURE 14).
Compared with atrial myocytes, PVs cells have similar
ICaL, ICaT, Ito, and NCX but lower current density of IK1, IKr,
and IKs, with inconsistent results available regarding INa
(576, 581). Interestingly, a hyperpolarization-activated
inward K1 current was reported in canine PVs cells, which
was highly sensitive to low submicromolar concentration
of Ba21 (579). Based on this finding, Kir3 subunits were
speculated to be involved as the channel background of
this current, and it was suggested that it may play a signifi-
cant role in atrial pathophysiology (579). This current, IK,
ACh, was enhanced in a conscious tachypaced dog AF
model, and its inhibition by tertiapin-Q resulted in a
marked reduction in the incidence of AF episodes (558).
In rat PV, a voltage-dependent Cl current
was also reported and suggested to contribute to
norepinephrine-induced automaticity in the PVs. (582).
PVs electrophysiology is also modulated by a wide variety
of drugs that are used in clinical practice including cele-
coxib, amiodarone, ranolazine, losartan, and enalapril
(583–587). Several factors and diseases, e.g., stretch
(585), electrolyte disturbances, sex differences, air pollu-
tants (H2S) (588), thyroid hormone (580), ischemia-reperfu-
sion (589), uremic substances, renal and heart failure, and
aging, have been reported to influence the electrophysiol-
ogy of PVs.
Recently, it was shown that factor Xa inhibitor anticoa-
gulants, which reduce the incidence of AF-related
stroke, also decrease the activity of rabbit PV cells, by in-
hibiting PAR1 and also diminish INaLate. Based on this, it
was speculated that they can modulate the occurrence
of atrial fibrillation (590).
Although it is generally accepted that PVs represents
an important trigger for arrhythmias, further research in
this field is still necessary to fully elucidate the role of PVs
in arrhythmogenesis and to develop new effective thera-
pies involving PVs in general (586, 587). Neverthe-less,
PV isolation by catheter ablation has become an estab-
lished therapeutic intervention in the management of par-
oxysmal and persistent AF (591, 592).
4.4. AV Nodal Action Potential and Conduction
Although they have similarities, AV node cells differ from
the SAN cells (593–595), with a lower spontaneous
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frequency and a more negative maximal diastolic poten-
tial (596, 597). The structure of the AV node, like the
SAN, includes a large variety of different cell types (598,
599), with different channel expression (600–603). In
the rat AV node, high expression levels of HCN4, Cav3.1,
Cav3.2, Kv1.5, Kir3.1, and Kir3.4 and low expression of
Nav1.5 and Kir2.1 mRNA were measured compared with
those observed in the ventricle (600). In rabbit AV node,
no or low expression of Nav1.5, Cav1.2, Kv1.4, KChIP2,
and RYR3 and high expression of Cav1.3 and HCN4
mRNA were reported (601). Like SAN cells, AV nodal
cells do not have functioning fast Nav1.5 INa channels,
and therefore their depolarization and impulse conduc-
tion depend on the function of ICa,L (565, 603). In AV
nodal cells, the expression and function of IK,ACh is par-
ticularly important (604, 605), since their activation via
the adenosine 1 or muscarinic receptors (606) hyperpo-
larizes the AV nodal cells, which slows or blocks impulse
conduction in the AV node (607, 608). In addition, aden-
osine and acetylcholine decrease ICa,L via Gi protein sig-
naling pathway, further decreasing the safety of impulse
propagation through the AV node. These are the princi-
pal cellular mechanisms that make intravenous adeno-
sine so useful in stopping AV nodal reentry tachycardia
(604). The T-type Ca21 channel is expressed and is
functional in the AV node as in the SAN (607). Indeed,
mibefradil, a potent ICa,T inhibitor, increased AV nodal
conduction time and even elicited second- or third-
degree AV block in isolated, blood-perfused dog hearts
(607). The slow conduction through the AV node is
physiological and provides a time lag for contraction
between the atria and the ventricles. AV nodal tissue
has diverse and different connexin 40, 43, and 45 distri-
bution compared with other parts of the heart (8), with a
complex and diverse structure, containing a dual faster
and slower impulse conduction pathway (594, 603,
609). This latter can provide the basis of fixed-rate
supraventricular reentry tachycardia as was elegantly
demonstrated in an early study in rabbits by Janse et al.
(610), and this tachycardia can be terminated by block-
ing ICa,L and IK,ACh and by adenosine (604, 611, 612).
AVN cells lack Ito and have background sodium inward
current flowing through a nonselective cation channel
(605, 613). These cells express functioning IKr, IKs, and If,
but If is not required for their pacemaking (614).
4.5. Purkinje Fiber Action Potential
Purkinje fibers play a pivotal role in impulse conduction
and propagation in the ventricles (615, 616). Purkinje
cells can also act as subsidiary pacemakers, and they
display a spontaneous diastolic depolarization, although
their frequency is normally inhibited by the higher-fre-
quency discharges of the SAN, causing overdrive
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
suppression. Purkinje fibers have a longer APD than do
ventricular cells, and this may have a protective function
against retrogradely propagating stimuli (615) but it can
also represent a source of arrhythmogenic repolariza-
tion inhomogeneity, even in the normal heart, which can
increase in diseased conditions or after drug exposure.
In certain pathophysiological situations, Purkinje fibers
can show triggered activities (617), such as EADs, DADs,
and cellwide ectopic Ca21 waves, in surviving tissue in
the border zone of an infarct (618). It was recognized
long ago that Purkinje strand fibers, which run close to
or on the surface of the endocardium, are less affected
by ischemia-induced tissue damage compared with ven-
tricular cells (118, 619). Purkinje fibers have been exten-
sively studied with the conventional microelectrode
(620) and the two-electrode voltage-clamp (621) techni-
ques. However, since cell isolation from cardiac Purkinje
tissue is particularly difficult, research in Purkinje fibers
has benefited less from the introduction of the patch-
clamp technique, despite its importance (622).
Purkinje fibers have a special role in impulse con-
duction, with their depolarization being about two to
three times faster (300–750 V/s) than in atrial or ven-
tricular (100–250 V/s) muscle preparations (623). The
fast depolarization is thought to be due to the abun-
dant expression of the TTX-sensitive Nav1.5 channel
isoform (85), but low density of TTX-sensitive neuronal
Nav1.1 and 1.2 Na1 channel isoforms may also signifi-
cantly contribute to INa in Purkinje fibers (624, 625).
Importantly, the relation between impulse conduction,
upstroke velocity (Vmax), and ionic currents is not linear
(626–628), and Vmax is not a direct measure of ionic
currents. INa in Purkinje fiber also seems to have a par-
ticular impact on repolarization, due to its relatively
large slowly inactivating component (12, 13, 82). Some
authors suggested that the skeletal muscle Na1 chan-
nel isoform Nav1.4 (78) while others suggested that
Nav1.7 subunits (85) were responsible for this slowly
inactivating component in Purkinje fibers; however,
this issue is not clarified and needs further investiga-
tions. In canine Purkinje fibers, connexin 40 is more
abundantly whereas connexin 43 is similarly
expressed compared with ventricular myocardium
(629): this can play a role in differences between their
conduction properties. The large phase 1 repolariza-
tion in Purkinje fibers (FIGURE 6) is caused by the fast
inactivation of INa and activation of Ito. Not only is Ito
larger than in ventricular muscle, but it inactivates
somewhat slower and recovers from inactivation >10
times slower than that in the ventricular muscle cells
(630). This behavior of Ito is attributed to the different
expression of Ito a- and b-subunits in dog ventricular
muscle and Purkinje fibers (141, 157). In human ventricu-
lar myocytes Kv4.3 channel subunits dominate,
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whereas in human Purkinje fibers abundant Kv3.4 and
Kv4.3 expressions were reported, with marked differ-
ences also in b-subunit (KChIP2, KChaP, KCNE2)
expression patterns (158). The slow Ca21-dependent
Ito2 Cl current was also described in rabbit Purkinje
fibers (631) and implicated in phase 1 repolarization
and DAD formation in sheep Purkinje cells (632), since
at potentials more negative than the chloride equilib-
rium potential chloride channels conduct depolarizing
current. The L-type ICa is well expressed in Purkinje
fibers and, unlike in ventricular myocytes, it is carried
not only by Cav1.2 but also by Cav1.3 channels (633),
and this may result in some differences in the proper-
ties of ICa,L between ventricular and Purkinje myocytes.
In the canine Purkinje fiber, there is larger T-type ICa,
with a higher Cav3.2 expression than in ventricular and
atrial myocytes (633). Based on this, it was speculated
that T-type ICa has an important role in Purkinje fibers,
by contributing to both depolarization and pacemaker
function (634). IKr, IKs, calcium-activated K1 currents, as
well as IK1 have been described in Purkinje fiber (323,
635, 636). Accordingly, inhibition of IKr and IK1 signifi-
cantly lengthens repolarization, even more so than in
the ventricular muscle (615). However, the inhibition of
IKs does not change repolarization of Purkinje fibers in
the normal situation (256). This is not surprising, since
Purkinje fibers have a plateau voltage less positive
then 0 mV, which is below the activation threshold of
IKs. However, at high frequencies and a high level of
sympathetic activation, the plateau level is shifted to-
ward more positive values, increasing both IKs ampli-
tude and speed to such a level to influence both
repolarization and pacemaker function (256).
Unlike ventricular but similarly to atrial muscles,
Purkinje fibers express IK,Ach and Kir3.1 GIRK channel
subunits, thus responding with an APD shortening
upon acetylcholine administration (637). The pace-
maker If current is robust in Purkinje fibers (638–640),
where it was first discovered (524), and it plays an im-
portant role in the pacemaker function. Later, a K1 cur-
rent, IKdd, was also described in Purkinje fibers (640),
deactivating at more positive potentials than If and
thus having an additional role in the pacemaker func-
tion in Purkinje fibers. In addition, spontaneous Ca21
release-induced intracellular Ca21 waves can also
modulate normal Purkinje fiber pacemaker activity
(641). This may have particular importance in ectopic
automaticity of Purkinje fibers surviving myocardial in-
farction (618). Recently, significant SK2 current and
channel expression were described in rabbit Purkinje
fibers, and an important role for SK2 current in Purkinje
fiber repolarization was suggested (323).
Free-running Purkinje strands emerging distally into
ventricular muscle constitute a relatively large-
1113
 VARRÓ ET AL.

FIGURE 15. Quinidine-induced early afterdepolari-

zations (EADs) in canine Purkinje fibers propagate to
the ventricular myocardium. Top: multiple EADs origi-
nating from Purkinje fiber (ME1) and propagating to
the ventricular myocardium, recorded at position
ME2. Bottom: experimental setup and the positions
of the 2 microelectrodes (ME). (Modified from Ref.
643 with permission.)

resistance connection (642), and a high degree of sink
for current flow, and a more favorable site of conduction
block than other parts of the healthy myocardium. Also,
because of the weaker electrotonic coupling, the disper-
sion of repolarization here can be far greater than in
other places (201). Indeed, it was experimentally proven
that EADs in free-running Purkinje strands could elicit
extrasystoles in ventricular muscle (643) by electrotonic
interaction (FIGURE 15), which is unlikely to happen in
healthy and well-coupled regions within the ventricular
wall.
Since Purkinje fibers are considered particularly im-
portant in arrhythmogenesis (644), further research
studying Purkinje fiber ventricular muscle junctions or
subendocardial layer containing a mixture of Purkinje
fibers and ventricular muscle would offer promising
results.
4.6. Ventricular Action Potentials: Transmural and
Regional Differences
Ventricular action potentials (FIGURE 6) in humans and
in most mammals have a positive (120 to 130 mV) and
relatively long plateau phase, with a small or pro-
nounced phase 1 repolarization and notch afterwards,
depending on their transmural site of origin (subendo-
cardial, midmyocardial, or subepicardial) (143, 645, 646).
Regardless of their origin, they express large INa and
ICa,L and relatively weak but persistent INaLate (80). These
currents provide robust depolarization and thereby
secure impulse conduction. In addition, by counterbal-
ancing outward potassium currents, e.g., Ito, IKr, IKs, and
IK1, they participate in the maintenance of the plateau
phase (FIGURE 6). As mentioned above, IKur and IK,Ach
are expressed weakly or not at all in the ventricles.

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 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
There are several reports indicating electrophysiolog-
ical differences between the right and left ventricle. In
dog hearts, it was found that left ventricular myocytes
had longer APD than those in the right ventricle (647,
648). Also, right ventricular myocytes exhibited more
pronounced phase 1 repolarization and larger Ito (648,
649) and increased IKs (648). It was also reported that
canine subepicardial and subendocardial myocytes in
the left ventricle possessed larger INa with higher Vmax
compared with those in the right ventricle (650). The
authors suggested that these differences provided a
mechanism for the right ventricular manifestation of
Brugada syndrome (650).
Almokalant, a drug with APD-prolonging effects,
increased interventricular dispersion of repolarization
that was associated with the occurrence of EADs and
torsade de pointes arrhythmia in dogs with chronic AV
block (647). In these dogs, the APD prolongation was
larger in the left ventricle than in the right ventricle (647).
The opposite was observed in guinea pigs, i.e., the APD-
prolonging drugs dofetilide and quinidine lengthened
APD more in the right ventricle (651). These findings
highlight important differences among species in their
responses to drugs with repolarization-prolonging effects.
In humans, similarly to dogs, the APD is longer in the left
ventricle with slower adaptation to increased heart rate
than in the right ventricle (652). These interventricular dif-
ferences in repolarization are not sufficient to cause
arrhythmias in the normal heart; however, in the presence
of an ischemic region at the left ventricle (LV)-right ventri-
cle (RV) junction, the interventricular APD heterogeneity
and different AP rate adaptation promote reentry arrhyth-
mias (652).
Important regional electrophysiological differences
were described in the dog ventricle long ago (653),
transmurally (654), regionally (655), and in the basoapi-
cal direction (143). These differences are due to substan-
tial differences in the density of expression of various
transmembrane ion channels, shaping the action poten-
tials accordingly in the different regions of the ventricles
(645). Transmural differences in repolarization have
been extensively studied and are well explored (656). It
has been found that subepicardial cardiomyocytes ex-
hibit a large phase 1 repolarization and Ito compared
with those in the subepicardium (657). Myocytes iso-
lated from the midmyocardium, called M cells (654), are
variable in this respect, but they are still characterized
by a distinct phase 1 repolarization and a relatively large
Ito (654), INaLate (658), and NCX (659) and small IKs (660).
All these ion current characteristics contribute to the lon-
ger APD of M cells compared with subepicardial and
subendocardial myocytes leading to a substantial trans-
mural dispersion of repolarization (656). Augmented
transmural dispersion of repolarization has been
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considered a contributor to ventricular tachycardia and
fibrillation development in patients with Brugada syn-
drome, acquired and congenital LQT syndromes, short
QT syndrome, and catecholaminergic polymorphic ven-
tricular tachycardia (CPVT) (656). However, these differ-
ences in transmural repolarization are relatively small in
the intact, undiseased ventricles (642, 661), since the
neighboring myocytes are well coupled. Accordingly,
experimental evidence suggests that in the intact heart
the transmural dispersion of repolarization is consider-
ably less (642, 661, 662) than that reported in tissue sli-
ces and perfused wedge preparations (663, 664).
Ther-efore, it was argued that it is unlikely that a large,
significant repolarization gradient between the sube-
ndocardium, M cells, and subepicardium existed, con-
tributing to EADs or arrhythmias (665). However, in
pathological settings and/or drug treatment and at
Purkinje fiber ventricular junctions (FIGURE 15), APDs
can lengthen in a nonuniform manner and cellular
coupling can deteriorate, thus resulting in a substrate
for serious ventricular arrhythmias.
Apico-basal electrophysiological differences have
also been described: the APD was shorter and phase 1
repolarization was markedly larger in canine cardiomyo-
cytes isolated from the apical region than in those from
the basal region (655). In the same study, larger Ito and
IKs were observed in apical than in basal cardiomyocytes
(655). In this context, the apico-basal and the antero-
posterior, and not the transmural, repolarization gra-
dients have been considered to contribute to the gener-
ation of the T wave (665, 666).
Since idiopathic ventricular arrhythmias often origi-
nate from the right and left ventricular outflow tracts
(RVOT and LVOT), the electrophysiological properties of
these regions have also been investigated (667–670). It
was found that rabbit right ventricular myocytes from the
apex had longer APD, larger Ca21 transients, higher
Ca21 stores, increased INaLate and Ito, but smaller IKr, L-
type Ca21 current, and NCX than RVOT myocytes (671).
These differences were associated with increased inci-
dence of DADs induced by pacing (671). Myocytes from
the LVOT exhibited longer APD, larger INaLate and NCX,
and smaller Ito and IKr than those from the RVOT (669).
4.7. Species-Dependent Differences in Action
Potentials
Arrhythmia research is often performed in different ani-
mal models, but its ultimate goal is to understand the
mechanisms in humans and to prevent, or successfully
treat, arrhythmias in patients. Therefore, it should always
be kept in mind how experimental results can be extrap-
olated to humans. It is often overlooked that rodents
(rats and mice) have ion channel expression profiles
1115
 VARRÓ ET AL.
distinctly different from humans (40, 672). This also
results in different cardiac electrophysiology properties
(672, 673), especially during repolarization (FIGURE 12).
Mice and rats have a high heart rate (600 and 400
beats/min, corresponding to cycle lengths of 100 and
150 ms), 10-fold faster than in humans. As a conse-
quence, mice and rats have very short ventricular and
atrial action potentials, to provide enough time for dias-
tole. These short action potentials result from the pres-
ence of transmembrane currents like Ito and IKur (144). In
the ventricles of larger mammals (guinea pig, rabbit,
dog, etc.) or humans, these channels are expressed less
or not at all and also have a different molecular back-
ground and functional role. Action potentials in mice or
rats lack a plateau phase (144); therefore IKr and IKs are
not likely to operate despite the fact that expression of
mRNA for these channels has been reported (674).
Notably, both IKr and IKs were observed in neonatal
mouse ventricle, but after further development neither
IKr nor IKs was detected in adult mouse ventricular myo-
cytes (675). Also, inward currents like ICa and INa have dif-
ferent impact on ventricular repolarization than in other
mammals. Consequently, drugs can have marked spe-
cies-dependent effects on action potentials as demon-
strated with an example of IKr inhibition in FIGURE 13.
These fundamental differences mean that mice and rats
can only be properly used in arrhythmia and related phar-
macological research if the limitations of the models are
described. As FIGURE 13 illustrates, pharmacological in-
hibition of specific potassium channels, such as IKr, Ito,
and IKur, elicits strikingly different effects on ventricular
repolarization in the rat, a commonly used laboratory ex-
perimental animal, compared with humans. Despite this,
hundreds or thousands of papers using mice or rats have
been published on this topic, because these animals are
relatively cheap and easy to house. In addition, trans-
genic manipulations of transmembrane ion channels are
almost entirely applied in mice (674), with very few excep-
tions (676–678). This makes the mouse a favorable tar-
get, despite the fact that the mouse can be useful to
study sodium and calcium channels and connexins but
not potassium channels.
There are far less consistent data on characteristic
species-dependent differences in atrial action poten-
tials and the underlying specific transmembrane cur-
rents. As FIGURE 10 shows and several papers
indicate (297, 645, 679, 680), most of the species
commonly used in experimental laboratories exhibit
similar action potentials and underlying currents, with
the atrial action potentials lacking a plateau phase,
except in humans (556, 681). Human atrial tissue sam-
ples, unlike ventricular samples, can be obtained from
cardiac surgery departments (from patients undergoing
open heart surgery for coronary artery bypass grafting,
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heart valve repair or replacement); therefore, human atrial
cellular electrophysiological data are abundant, some-
what limiting the need for such studies in experimental
animals.
Although the species differences in the shape of ven-
tricular action potentials are most striking between small
rodents and humans, important species differences also
exist in the action potentials between humans and other
mammals. Guinea pig ventricular muscle, unlike human,
does not express Ito and does not exhibit a prominent
phase 1 repolarization (144, 145); however, it expresses
large IKs with distinct gating properties compared with
human (3, 214, 249). Rabbit Ito, unlike human, is con-
ducted mainly by Kv1.4 channels, and as a consequence
cycle length-dependent APD is markedly different from
that observed in human ventricle (682). Pig ventricular
muscle exhibits Ca21-activated Ito chloride current that
shapes phase 1 repolarization (683) but lacks 4-AP-sen-
sitive Ito despite abundant expression of Kv4.2 and
KChIP2 mRNA and proteins (684). The dog ventricular
muscle was found to express a considerably higher den-
sity of IK1 compared with human (685). This results in a
stronger repolarization reserve and consequently less
APD prolongation upon IKr inhibition in the dog ventricle
compared to human. All of these differences have a par-
ticular significance when drug effects and pathophysio-
logical electrophysiological alterations are extrapolated
from animal models to humans.
Human induced pluripotent stem cell-derived cardiac
myocytes (HiPSCs) are increasingly used in cellular ar-
rhythmia research (686, 687). This new approach is
promising and expanding rapidly (688). At the present
stage, however, it seems that HiPSCs have some impor-
tant limitations (689). Although in HiPSCs experiments
can be performed relatively fast, at present they cannot
provide a substitute for carefully applied animal prepara-
tions. The so-far unresolved problems with HiPSCs are
the following: data include cardiomyocytes that have not
fully differentiated, still showing an immature phenotype
(690, 691), and the cells spontaneously beat and often
have a relatively low resting potential because they lack
IK1 and also have low upstroke velocity (692–694).
However, an interesting study suggests that the low
resting potential and reduced IK1 are not necessarily in-
herent characteristics of HiPSC-derived cardiomyocytes;
rather, these observations might be due to technical
issues related to performing patch clamp on the rela-
tively smaller cells (692). Also, HiPSC sarcomeres are
disorganized, and their shapes are different from those
of the adult cells (691). So far, atrial and ventricular-like
HiPSC cells have been successfully generated, whereas
SAN, AV node, or Purkinje-like stem cell generation has
been unsuccessful (691). However, HiPSC-derived myo-
cytes from patients with defined mutations using
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS

CRISPR/Cas9-edited cells can mimic diseases (688, 5. COMPUTER SIMULATIONS OF ACTION

695–698) that are often hard or impossible to recreate POTENTIAL
properly in animal experiments. Recent efforts to culture
and continuously pace HiPSC-derived cardiomyocytes The vast quantity of experimental data describing struc-
cultured in collagen gels as “engineered heart tissue” ture and function of myocytes has enabled the develop-
represent a new two-dimensional (2-D) and three- ment of computer electrophysiology models capable of
dimensional (3-D) approach (699–701), since it resem- replicating action potential and conduction properties in
bles more the mature myocardium. Future research in a variety of species including human. Thus, the last 60 yr
this area, however, may revolutionize the field, opening have seen huge progress in our ability to model and sim-
new horizons for arrhythmia research. ulate the electrophysiology of the heart. Cellular

INa INaK INaCa IKs

IKb

I(Ca)Cl
INaL INab IK1 IKr
Ito
INaCa
Jrel IpCa
Jtr
IClb
ICaL

Jup ICab
Jleak

Jdiff ICaL

50 x 10-4
4
Membrane potential (mV)

3
0
Cai (mM)

-50

-100 0
0 100 200 300 400 500 0 100 200 300 400 500
Time (ms) Time (ms)

FIGURE 16. Structure of the Tomek, Rodriguez—following O’Hara–Rudy dynamic (ToR-ORd) ventricular myocyte model. The cell consists of 4 compart-
ments: main cytosolic pool of ions, SS [junctional subspace along T tubules, where Ca21 influx via L-type Ca21 current (ICa,L) and Ca21 release from the
sarcoplasmic reticulum (SR) interact, and where local calcium concentrations may reach much higher values than in the main cytosolic compartment], and
2 subcompartments of the SR [network (NSR) and junctional (JSR)]. I, ionic currents; J, ionic fluxes. Clouds correspond to calcium buffers. Key effects of
Ca21-calmodulin kinase-II on ionic currents and fluxes (such as ICa,L or SR release and reuptake) are also represented (717). Below the model diagram the
simulated membrane potential and calcium transient are shown, in agreement with experimental data. RyR, ryanodine receptor; SERCA, sarcoplasmic
reticulum CaATPase; CSQN, calsequestrin; ICab, background calcium current; I(Ca)Cl, calcium-sensitive chloride current; IClb, background chloride current;
IK1, inward rectifier potassium current; IKb, background potassium current; IKr, rapid delayed-rectifying potassium current; IKs, slow delayed-rectifying potas-
sium current; INa, sodium current; INab, background sodium current; INaK, sodium-potassium pump current; INaL, late sodium current; INaCa, sodium-calcium
exchange current; Ito, transient outward potassium current. Reproduced from Ref. 717 with permission.

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 VARRÓ ET AL.
computational models of different species and cell types
are now available, through data and knowledge integra-
tion in an iterative process between experimental and
computational work (702). The first models of a cardiac
cell were the Noble model of the Purkinje cell (703) and
the Beeler and Reuter model of ventricular muscle fiber
(704), following the pioneering work of Hodgkin and
Huxley in giant squid axon (705). Since those times,
computer models have developed tremendously in their
capabilities, robustness, and applications, ranging from
understanding of arrhythmogenesis (706–712) to drug
safety testing in industrial and regulatory settings (713–
715).
Simulations with computational models offer perfect
observability and controllability, which help to overcome
limitations in experimental models. They can be viewed
as an organized and formalized literature review that
can be probed through simulation studies. They provide
mechanistically informed and tractable predictions,
which can then inform additional experiments and be
linked back to existing knowledge of physiological
mechanisms. At the same time, when simulations with a
computational model fail to reproduce a particular phe-
nomenon, gaps in knowledge or inconsistencies in the
state of the art can be identified. This may be an oppor-
tunity for discovery of key factors or processes not
included in the model, which may be critical for specific
phenomena in living cells (716).
A computational model of cardiac cellular electro-
physiology typically consists of a set of differential
equations describing the mechanisms of transmem-
brane ionic transport and excitation-contraction cou-
pling. Today’s models are commonly separated into
multiple subcellular compartments to allow local-
ized calcium signaling and diffusion {an example of
the structure of the recent human ventricular myo-
cyte model [Tomek, Rodriguez—following O’Hara–
Rudy dynamic (ORd) (ToR-ORd)] (717) is reproduced
in FIGURE 16}.
The most broadly used framework of modeling dis-
tinct ionic currents is the Hodgkin–Huxley equations
(705), where several independent “gates” (activation,
inactivation, etc.) of the respective current are formu-
lated based on experimental data; a combination of the
gates then determines the fraction of open channels.
This is subsequently combined with open channel con-
ductance and ionic driving force through the open chan-
nel to produce total current. Traditionally, single-pulse
square voltage clamp was used to collect data used to
create ionic current models. However, in some cases it
was shown that predictions based on such data do not
match behavior of the current under AP clamp, such as
in the late sodium current (693). Consequently, more
complex protocols such as two-pulse voltage clamp, AP
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clamp, or sine-wave protocols are also used to construct
models with complex gating properties (718, 719).
Similarly to the necessity of collecting more complex
data, a mathematical model of a current sometimes
requires more complex structure. There are data that
cannot be represented accurately with the Hodgkin–
Huxley equations, and a more sophisticated modeling
method is needed. In such cases, Markov models are
typically used instead, where distinct states of a channel
are represented (e.g., open, closed, inactivated by volt-
age, inactivated by drug, etc.) along with probabilities of
transitions between these states (719–721). Recently,
electrophysiological measurements were combined
with molecular dynamics simulation (<0.25 Å) of the
channel behavior to simulate ionic currents, which may
allow simulations of mutations and drug effects repre-
senting the actual molecular processes (722, 723).
5.1. Ventricular Models
Given the relevance of ventricular fibrillation, the field of
computational cardiac electrophysiology has focused
predominantly on ventricular cardiomyocytes. A mile-
stone in the development of ventricular models was the
Luo–Rudy model of a guinea pig cell (707, 708), setting
standards in how models are constructed and evaluated
based on experimental data and how such models are
used to study physiological behaviors. These models
include the key ionic currents, such as fast sodium cur-
rent, L-type calcium current, delayed repolarization cur-
rent, sodium-calcium exchanger, and the inward rectifier
potassium current. The main features of calcium handling,
including sarcoplasmic reticulum release and reuptake,
are also incorporated. The model was subsequently used
to study the interplay of ionic currents and ion concentra-
tions in formation of early and delayed afterdepolariza-
tions (707, 708). The Hund–Rudy canine model (724)
separated the delayed rectifier currents into rapid (IKr)
and slow (IKs) components (as in Ref. 725), added two
components of transient outward current (Ito,1 and Ito,2),
and included a model of CaMKII activation and signaling,
studying the impact on rate-dependent behaviors. In
addition, it introduced an intracellular subcompartment:
the junctional subspace (where L-type calcium channels
and ryanodine receptors colocalize and where calcium
concentration reaches a much higher value than in the
bulk cytosol), which is also a standard in today’s models.
The model was subsequently updated (726) and used to
study the effect of disease (727) and of b-adrenergic stim-
ulation (728).
Another very influential model, created in 2004, is the
Shannon rabbit model (729), which also separated differ-
ent components of delayed rectifier current and
included the junctional subspace and which focused
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
predominantly on an accurate representation of calcium
handling. The model was subsequently modified to
improve its rate-dependent behavior (721) and was used
to study alternans. Interestingly, even though a large
proportion of experimental cardiac research is carried
out in rodents, there are very few detailed rodent mod-
els. Relatively recent models by Bondarenko et al. (730)
and Morotti et al. (731) thus provide an important tool in
complementing rodent-based experimental research,
and they may be used to gain insight into species differ-
ences (40).
5.2. Human-Specific Ventricular Models
Modeling and simulation of human ventricular electro-
physiology are crucial subcategories of computational
cardiac electrophysiology. The central species difference
between human and other mammals is the high reliance
of human cardiomyocytes on IKr for repolarization, unlike
in other species, where the also relatively highly
expressed IKs provides an additional repolarization
reserve. This is of utmost importance, e.g., in the study of
drug safety, where hERG/IKr blockers may cause a much
greater APD prolongation in humans than in animals
(685). The specifics of human repolarization thus warrant
the development of specifically human-driven computer
models. The first of these that gained wide popularity
was the pair of models by ten Tusscher et al. (732, 733). A
second family of widely used human ventricular myocytes
is the model by Grandi et al. (734) and the Carro–
Rodríguez–Laguna–Pueyo (CRLP) model that followed it,
focusing on rate dependence and behavior in hyperkale-
mic conditions (735). Possibly the currently most popular
human ventricular model is the one by O’Hara et al. (ORd)
(736), created and evaluated with a wide range of experi-
mental data, many of which were collected specifically for
the purpose of the model development. The ORd model
incorporates CaMKII signaling and is capable of manifest-
ing early afterdepolarizations among other features.
Together with its humanlike mixture of repolarization cur-
rents, it has become, with various modifications, a domi-
nant model in the assessment of drug safety (713, 715)
and is a prime example of how computer modeling and
simulation may be used for regulatory purposes (737).
Recently, a new human ventricular myocyte model, ToR-
ORd, was published (717), improving on its predecessor
ORd in multiple aspects, such as similarity of the action
potential morphology to experimental data or the
response to sodium channel blockers. The model also
brought biophysical insight into properties of ICa,L and IKr,
which are important for the understanding of sodium and
calcium dynamics in ventricular myocytes.
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5.3. Other Tissue-Specific Modeling
As discussed in sect. 4 of this review, different tissues
manifest markedly different action potentials, achieved
by differential function of ionic currents. Cardiac models
reflect this, allowing tissue-specific simulations repre-
senting specific features of atrial, Purkinje, or sinoatrial
cells.
5.3.1. Atrial models.
Human atrial electrophysiology modeling and simula-
tions are active topics of research. Two prominent mod-
els of human atrial electrophysiology are by
Courtemanche et al. (738) and Nygren at al. (739), both
recapitulating specific AP morphology of atrial myo-
cytes. The Courtemanche model used the Luo–Rudy94
model as a starting point (708) but reformulated the ionic
currents according to human and canine data from atrial
myocytes. The model was used to understand the im-
portance of L-type current inactivation in APD shorten-
ing in the S1S2 protocol and to gain insight into the role
of Ito in variability of atrial AP morphology. The Nygren
model (739) was mostly based on a similar set of data,
but it used a different model as the starting point (740).
Its analysis provided insight into differences between
human and rabbit repolarization, focusing on the role of
the sustained outward potassium current. More recent
models, adding and studying ionic homeostasis, addi-
tional currents, and signaling, are described in Refs.
741–743. We refer the reader to more comprehensive
reviews (744–746) on atrial modeling and simulation.
5.3.2. Purkinje cell models.
Even though Purkinje fiber cells were the focus of the
first cardiac electrophysiology models (703), progress
in this area has been irregular. In 1985 an updated
model was published, describing both electrophysiol-
ogy and changes in ionic concentrations (639), but the
focus subsequently shifted toward other cell types
discussed above (747). In recent years, the interest in
Purkinje fibers has been reinvigorated, producing
models focusing on their role and changes in heart
failure (748), the electrophysiological basis of rabbit
Purkinje electrophysiology (749), and the importance
of Purkinje fibers in arrhythmogenesis (750, 751). The
very recent Purkinje model by Trovato et al. (752)
introduced a comprehensive calibration to human
data in a wide range of conditions, bringing insights
into Purkinje cell EADs and abnormal automaticity
such as following IK1 reduction or If increase.
1119
 VARRÓ ET AL.
5.3.3. Sinoatrial cell models.
Sinoatrial cell modeling and simulation has also made sig-
nificant progress in recent years in both rabbit (753, 754)
and human (755), enabling investigations into the ionic ba-
sis of the cardiac pacemaker in normal and disease condi-
tions including the effect of mutations (281, 755, 756).
5.3.4. HiPSC models.
An additional cell type that is gaining increasing popular-
ity is human-induced pluripotent stem cells (HiPSCs),
which offer a new human-based paradigm in experimen-
tal research. Computer modeling and simulation of
HiPSC is an important tool complementing the experi-
mental system. This was pioneered by Paci et al. (757)
and is now an active research field (758, 759).
5.4. Different Modeling Scales
In sect. 5.3, we focused predominantly on cell-level
modeling, where one set of equations describes the
cellwide current. This usually provides a good trade-off
of relatively high biological detail but still affordable
computational time (<1 s per 1 action potential). For spe-
cific purposes, it may be necessary, however, to either
increase or decrease the level of detail. In particular,
detailed phenomena driven by cellular calcium handling
(such as calcium waves and resulting delayed afterde-
polarization as well as some mechanisms of calcium-
driven alternans) usually require a high degree of detail
(760–762). In such models, a single cell is subdivided
into small (microscale or even nanoscale) cuboids that
may represent membrane, calcium release units from
the SR, cytosol, etc. and are coupled together to repre-
sent the cell. Such a level of detail, however, consider-
ably increases computational time, such as hours
(microscale models) or more than a day (nanoscale) for
several beats on a personal computer. On the other
side of the spectrum of model complexity are models
such as the Fenton–Karma (763) and minimal ventricu-
lar (MV) (764) models, which are more than an order of
magnitude faster to simulate compared with biologically
detailed cellular level models. This makes such models
an attractive tool, for example, model personalization
using clinical electrophysiological recordings (765) or
when tissue properties (rather than ionic properties) are
the target of the investigations (766, 767).
5.5. Variability in Computer Models
In recent years, representing variability in cardiac models
has emerged as a key new concept (50, 768–773). There
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are multiple sources of variability in experimental and clin-
ical data, caused by both intra- and interheart differences
as well as differences in experimental settings and/or
measurement techniques (50). One of the techniques to
investigate potential causes and modulators of biological
variability is the use of populations of models rather than
a single generic computational model (768, 774, 775).
Populations of models are ensembles of models sharing
the same structure based on a particular cardiomyocyte
model (such as the O’Hara–Rudy model) but with varia-
tions in model parameters, such as the conductances of
ionic currents. To achieve plausible populations, a calibra-
tion to experimental or clinical data can be carried out
(768): e.g., a model is accepted in a population only if its
action potential morphology and calcium transient prop-
erties fall within an experimentally observed range. Such
calibrated populations have proven to be useful in the
study of hypertrophic cardiomyopathy (776) and atrial fi-
brillation (775, 777) and for drug safety assessment (715,
775). An intrinsic limitation is that a plausible phenotype
may be produced by an unplausible mechanism and/or
by a biologically unrealistic combination of conductances
of ionic currents. More comprehensive data collection,
reporting, and understanding of biological variability is
thus an important future step for the fields of both experi-
mental and computational cardiac electrophysiology.
6. CELLULAR ARRHYTHMIA MECHANISMS
6.1. Depolarization Abnormalities
Impaired depolarization capability in cardiomyocytes can
reduce conduction safety, providing proarrhythmic sub-
strate and potentially contributing to conduction block and
reentry arrhythmia. One example of depolarization abnor-
mality leading to reentry arrhythmia is the Brugada syn-
drome, caused by the loss of function of SCN5A (778,
779). It should be noted, however, that in patients with
Brugada syndrome the mechanisms of arrhythmia are
more complex, since decreased function of L-type ICa and
enhanced function of Ito also contribute to the develop-
ment of phase 2 reentry (780), due to enhancement of dis-
persion of repolarization across the ventricular wall (779).
Ischemia can cause regional membrane depolariza-
tions, which indirectly decrease the strength of INa by
eliciting partial or full channel inactivation and result in
slowing of impulse conduction or unidirectional or bidir-
ectional conduction block. All of these factors are con-
sidered important in arrhythmogenesis. However, their
detailed discussion is beyond the scope of this review,
since they are described by others in great detail (31,
781–785). Drugs that inhibit INa can have similar effects
and can also cause reentry arrhythmias (202, 786, 787).
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
Upregulation of the If current (788) and HCN channels
(789) in the ventricles and atria (790) was reported in HF
(789) and HCM (791, 792). These changes can cause
abnormal myocardial depolarizations, and they can
relate to increased incidence of ectopic beats, providing
possible triggers for arrhythmias in an environment
where dispersion of repolarization (arrhythmia substrate)
is already augmented by structural heart disease.
6.2. Triggered Automaticity
Abnormal myocardial automaticity (formation of prop-
agating spontaneous action potential) is an estab-
lished trigger contributing to arrhythmia onset (26).
One particular type of such automaticity closely linked
to disturbance of normal cellular electrophysiology is
the so-called “triggered automaticity,” which requires
preceding action potentials that are essential for the
subsequent spontaneous firing (793). Depending on
the temporal relationship between such depolariza-
tion and the preceding action potential, triggered au-
tomaticity is typically separated into early and delayed
afterdepolarizations.
6.2.1. Early afterdepolarizations.
Early afterdepolarization (EAD; FIGURE 10, A and B) is
characterized by depolarizing potential changes occur-
ring before the termination of the preceding action
potential during phase 2 or phase 3 repolarization.
EADs are usually generated when action potential dura-
tion is excessively prolonged, e.g., when IKr is impaired.
As a consequence of the lengthened action potential,
those L-type calcium channels that have already recov-
ered from inactivation can reopen, and some of the cal-
cium channels carry a Ca21 window current (707, 708),
causing positive voltage oscillations during the plateau
(phase 2 EAD) or terminal repolarization (phase 3 EAD).
The Luo–Rudy studies (707, 708) also proposed a sec-
ond type of EADs, phase 3, resulting from spontaneous
calcium release during repolarization, which then trans-
lates into depolarization via NCX. The relevance of this
mechanism was subsequently demonstrated experi-
mentally in Purkinje fibers (131). This type of EAD strongly
resembles delayed afterdepolarizations in its mecha-
nism but differs in the timing (during AP vs. after AP).
Both types of EADs are rate dependent, with the reacti-
vation-driven mechanism appearing predominantly at
slow pacing, whereas the release-driven EADs occur at
fast pacing (794).
In general, both the L-type calcium current and NCX
are known to act synergistically in EAD formation (795,
796), and the controllability of computational models
has been used to understand their interplay. For
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example, Kurata et al. (797) demonstrated how NCX con-
tributes to EADs in the popular O’Hara–Rudy model (736)
via two distinct mechanisms. First, the influx of calcium via
the L-type calcium current upon its reactivation translates
into calcium efflux via NCX and thus additional inward
current (which can, in turn, promote further activation of L-
type calcium current). Second, NCX expressed adjacent
to L-type calcium channels acts as a “sanitizer” of calcium
in the cellular region, removing calcium ions from the
junctional subspace during repolarization. This may sub-
sequently reduce the calcium-dependent inactivation of
L-type calcium current, facilitating earlier reactivation. The
insight into EAD origins is not limited to L-type calcium
current and NCX; nonequilibrium gating of late sodium
current was implicated in EAD formations (798). The
increased availability of data on signaling pathways has
also enabled computationally driven insights on how
EADs are facilitated via CaMKII- or PKA-driven pathways
(799). This is particularly important for our understanding
of EADs in disease conditions such as heart failure, where
these pathways are dysregulated.
One interesting involvement of IKr in EAD formation
beyond the role in APD prolongation lies in its dynamic
of activation and reactivation. Lu et al. (719) used a range
of electrophysiological protocols to demonstrate an in-
triguing interplay of IKr activation, inactivation, and recov-
ery from inactivation, which leads to rapid increase of IKr
during late-plateau reactivation, such as during an EAD.
Such an increase in repolarizing current would be
expected to counteract and potentially outweigh depo-
larizing currents, potentially preventing the formation of
a larger-amplitude EAD.
6.2.2. Delayed afterdepolarizations.
The delayed afterdepolarization (DAD) is characterized
by depolarizing potential changes following the termina-
tion of the preceding action potential (129, 130, 632) dur-
ing diastole (FIGURE 10C). DAD is generally attributed
to calcium-sensitive depolarizing currents after sponta-
neous Ca21 release from the SR during Ca21 overload,
or CaMKII-dependent phosphorylation (800, 801), which
is promoted by diseases like chronic AF, ischemia, heart
failure (801–803), and catecholaminergic polymorphic
ventricular tachycardia (CPVT) or drugs like digitalis. The
most important calcium-sensitive current implicated in
DAD formation is the forward-mode NCX, but a role for
the calcium-sensitive chloride current has also been
suggested (804). The calcium-induced depolarization is
opposed primarily by IK1, which tries to maintain resting
potential (805). When the depolarization induced by cal-
cium-sensitive currents is of sufficient magnitude, over-
coming IK1, it activates INa, triggering a new action
potential. Automaticity occurring in the pulmonary veins
1121
 VARRÓ ET AL.
and in the myocytes represents important abnormal
impulse formations, and at present it seems that their
cellular mechanisms are complex, including the possibil-
ity of DAD and EAD generation as well (FIGURE 14).
The spontaneous calcium release is a stochastic phe-
nomenon, represented by calcium sparks (806, 807)
and intracellular calcium waves (807–810), and multiple
calcium release sites need to synchronize to produce a
cellwide calcium release (811, 812). The stochastic nature
of such events as well as generally limited controllability
and observability of subcellular calcium handling in the
experimental setting, complicate detailed understanding
of their origins. On the other hand, computer models
(736) offer excellent controllability and observability and
thus are a popular tool to understand origins of sponta-
neous calcium release and ultimately DADs. Increasing
availability of subcellular experimental data has enabled
the construction of spatially detailed models, where the
cell is subdivided into up to hundreds of thousands of
subdomains with separate clusters of potentially sto-
chastic ryanodine receptors (760, 813, 814). As a result,
such models can give very detailed predictions, eluci-
dating how originally random calcium sparks are
recruited into calcium waves and ultimately DADs but
also giving explanations for DADs that do not rely on cal-
cium waves (814).
6.2.3. From afterdepolarizations to arrhythmic
behavior.
One important aspect of triggered automaticity is that
the role of EAD and DADs in arrhythmogenesis is most
likely overestimated in single-cell experiments versus
the intact heart. Even in relatively poorly coupled tissue,
electrotonic interactions with neighboring cells will
decrease the depolarization produced by an EAD or a
DAD. However, moderate uncoupling will decrease the
electrotonic interaction between a focus and the sur-
rounding cells and can actually favor action potential
propagation (815).
Computer simulations studies have significantly con-
tributed to the understanding of the conditions under
which the afterdepolarizations of single cells may trans-
late into propagation throughout myocardium (816).
These modeling studies showed that when simulating
healthy cells and their afterdepolarizations, 70 cells
manifesting an afterdepolarization are needed to trigger
excitation in a fiber, 7,000 in 2-D tissue, and
700,000 in 3-D tissue. The specific numbers may very
well vary with numerical aspects related to the simula-
tions, such as the mesh discretization, but this neverthe-
less suggests the unlikeliness of EADs or DADs
promoting into tissue reactivation in a healthy tissue. At
the same time, however, the study by Xie et al. (816) also
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investigated the effect of gap junction uncoupling, fibro-
sis, and heart failure-like remodeling, showing that the
combined effect may reduce the number of cells
needed for an afterdepolarization-driven propagation by
two orders of magnitude. Specific patterns of uncou-
pling, such as thin strands of myocytes within postinfarc-
tion scars (817), which are similar to a fiber with regard to
coupling, may increase the relevance of afterdepolariza-
tions of arrhythmia even further. Another type of weakly
coupled tissue that might enable synchronization of
afterdepolarizations is the endocardial Purkinje ventricu-
lar junctions, as mentioned above (FIGURE 15).
In addition to promotion of extrasystolic reactivation
via cell decoupling, other mechanisms of synchroniza-
tion of afterdepolarizations are via stretch-activated
channels (818), current flow in the border zone of acute
ischemia (706), and partial chaos synchronization (369).
In a modeling study of calcium-driven afterdepolariza-
tions, it was suggested that calcium waves also syn-
chronize by calcium flux through gap junctions (819);
however, experimental results argued against this possi-
bility (811). Ultimately, simulation studies have shown that
the baseline risk of EADs may be considerably incr-
eased in diseased conditions (776, 820), further facilitat-
ing translation of a depolarization to tissue activation.
In the case of increase in intracellular calcium during
elevated sympathetic drive and/or diseases like heart
failure or catecholaminergic polymorphic ventricular
tachycardia (CPVT) (821), Ca21 overload may occur and
the SR can become leaky and release additional Ca21
(822). Mutations in the gene encoding the cardiac ryano-
dine receptor-related Ca21 release channels (RyRs) can
cause extrasystole and serious tachycardia such as
CPVT by abnormally releasing Ca21 from the SR (823)
into the cytosol on the response of catecholamines
which Ca21 would activate the electrogenic forward
NCX depolarizing cells beyond their threshold of activa-
tion. In a recent study, in a new model for CPVT in engi-
neered human tissue fabricated from human pluripotent
stem cell-derived cardiomyocytes, high-frequency pac-
ing and isoproterenol administration increased Ca21
wave propagation heterogeneity and elevated intracel-
lular [Ca21], leading to local depolarizations and conduc-
tion block (creating the arrhythmia substrate), and
subsequently resulting in reentry (700). Similarly to
CPVT, leaky ryanodine receptor-related Ca21 release
channels were also reported in heart failure (802, 824).
6.3. Frequency Dependence and Restitution
It was observed long ago that action potential duration
and impulse conduction depend on heart rate or on the
stimulation frequency. To study frequency-independent
repolarization changes caused by disease, drugs, or any
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS

Frequency dependent APD Abrupt change of cycle length

(electrical restitution)
320 300

280 FIGURE 17. Cycle length-dependent action

potential duration (APD90) changes (left) in
280 undiseased human (donor) ventricular mus-
260
cle (open symbols) and Purkinje fiber (filled
symbols) preparations. Right: the relation-
240 ship between APD90 and the preceding dia-
APD90 (ms)

APD90 (ms)
stolic interval (S1S2 restitution) in human
240 ventricle (open symbols) and Purkinje fibers
220
(filled symbols). Both protocols were meas-
ured with the conventional microelectrode
200 technique. APD90, APD at 90% repolariza-
tion. Unpublished observations from our lab-
200
Basic cycle length: 1000 ms oratory at the Department of Pharmacology
180
and Pharmacotherapy, University of Szeged,
Human Purkinje Human Purkinje Hungary.
Human ventricle Human ventricle
160
160
0 1000 2000 3000 4000 5000 0 40 80 120 160 200

Cycle length (ms) Diastolic interval (ms)

other factors, correction formulas have been used to esti- decreased safety or slowed impulse propagation.
mate QT intervals corrected for heart rate (QTc) on the Frequency-dependent APD changes show general pat-
ECG. At elevated heart rate, extracellular K1 accumula- terns (682, 825–830) that APD is short at high and longer
tion may occur in the clefts, slightly depolarizing the rest- at slow constant rates (FIGURE 17). The frequency de-
ing membrane potential that slows impulse conduction pendence of APD shows substantial species, tissue, and
and impairs safety of impulse propagation. At extrasys- regional variation and has important implication for
toles early following the end of ERP, repolarization is still arrhythmogenesis. At slower heart rate, APD can be
not fully terminated and Na1 and Ca21 channels are par- markedly prolonged, favoring triggered arrhythmias via
tially inactivated, resulting in less depolarizing current and EAD formation, and may also result in enhanced

R1: Steep restitution curve R2: Flat restitution curve

FIGURE 18. Arrhythmia development
APD (ms)

APD (ms)

via regional differences of the action

potential (AP) restitution. Left: consecu-
tive action potentials from a region with
a steep restitution curve (R ). Right: a
DI (ms) DI (ms) 1
region with flat action potential duration
S1 S2 S3 E1 E2 S1 S2 S3 E1 E2 (APD) restitution (R2). In both cases, S1–
S indicate 3 consecutive sinus node
3
stimuli followed by 2 extra stimuli (E1
and E2). In the case of steep APD resti-
tution, the E is able to propagate while
1
the conduction of E2 is blocked since
the refractory period of the developed
R1 R2
extra AP is sufficiently long. In contrast,
in the flat restitution region both extra
stimuli will propagate, since the APD of
the extra beats are not markedly pro-
longed. Therefore, these APs can reach
the R region (red arrow) and evoke
1
extra beats where the refractory period
has already been terminated (red
curves), establishing a circulating move-
ment of impulse propagation. DI, dia-
stolic interval.

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 VARRÓ ET AL.

FIGURE 19. Proposed mechanism of action potential (AP) alternans and arrhythmia development. The top sequence of the AP illustrates a proximal
and the bottom sequence a distal area of the left ventricle in respect of impulse propagation. On left, 2 consecutive normal (N) action potentials are
shown; the depolarization is readily conducted toward the distal area (black arrows), evoking further APs. When an extra stimulus (ES) with short cou-
pling interval reaches the proximal area, the evoked APs will be organized as a short-long-short pattern in both regions, establishing concordant alter-
nans (green curves). Under this condition, a second extra beat will evoke a short AP in the proximal region but a long AP in the distal area, since the
refractory period causes slowed impulse propagation (discordant alternans, orange curves). In this case the heterogeneity of the repolarization causes
a third extrasystole (red curve) in the proximal region to be blocked in the distal area (red dashed arrow), providing possibility for development of reen-
try arrhythmia. APD, action potential duration.

substrate for arrhythmias by increasing dispersion of rep-
olarization.
Electrical restitution refers to the recovery of the APD
of an interpolated beat as a function of time following the
previous beat. This changes in a manner that is some-
what similar to that seen (831) during frequency-depend-
ent steady-state APD changes (FIGURE 17, left). Despite
the similarities, there are important differences (FIGURE
17, right) that warrant the restitution being studied as a
separate rate-dependent property (826, 827, 832–835),
with importance for arrhythmia research (20, 836).
According to the restitution hypothesis, as the diastolic
interval increases because of the propagation of an extra
beat, the second extrasystole would encounter longer
APD/ERP and local conduction block may occur. A
steeper restitution curve would favor such an effect and
is considered proarrhythmic (20, 662, 837, 838), whereas
flattened electrical restitution curves would have an op-
posite consequence (FIGURE 18). Local regional differen-
ces in the APD restitution curves (839) may also favor
arrhythmogenesis (840). The ion channel background of
cycle length-dependent APD changes including APD res-
titution is attributed to the incomplete recovery and/or
deactivation of different inward (INa, ICa,L) or outward (Ito,
IKr, IKs, ICl) currents based on the gating behavior of these
channels (841, 842). In addition, intracellular ion concen-
tration changes for Ca21 and Na1 rapidly or slowly would
activate electrogenic NCX or Na1-K1 pumps. Also, fre-
quency changes can result in significant alterations in
extracellular K1 concentration in the extra-cellular clefts
(843), causing changes not only in depolarizing but also
in repolarizing transmembrane ionic currents. Detailed

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 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
discussion of these mechanisms is beyond the scope of
this review.
6.4. Repolarization Alternans and Temporal
Repolarization Variability
Repolarization alternans (FIGURE 19) at the cellular level
manifests as oscillation of long and short APD at rapid
heart rates, typically with concurrent oscillations in cal-
cium transient amplitude (712, 844). It has been demon-
strated that alternans can precede the formation of
arrhythmia in the heart (845, 846). Multiple studies and
reviews explain the mechanisms of arrhythmia induction
following alternans, typically linked to increased disper-
sion of repolarization (712, 847, 848). The spatial pattern
of alternans across cardiac tissue is typically “concord-
ant” at submaximal heart rates, i.e., the APD is either
simultaneously shortened or prolonged in all sites
(FIGURE 19) (712). However, further increase in the pac-
ing rate can elicit so-called discordant APD alternans
(FIGURE 19), when APDs at more distant regions can
alternate with opposing phases (712), substantially
increasing dispersion of repolarization and thereby the
substrate for arrhythmias (849).
The fact that repolarization alternans typically occurs
together with underlying oscillation of calcium transient
amplitude (850, 851) poses the question of which of
these two drives the other.
The first hypothesis suggests that the steep slope of
APD restitution is the alternans driver (852), and this
mechanism of arrhythmia is replicated by the ten
Tusscher–Noble–Noble–Panfilov model of human ven-
tricular myocyte (732, 733). As mentioned above, the ion
channel background of APD alternans is attributed to
the incomplete recovery and/or deactivation of different
inward (INa, ICa) or outward (Ito, IKr, IKs, ICl) currents based
on the gating behavior of these channels (841, 842). In
addition, intracellular ion concentration changes for
Ca21 and Na1 rapidly or slowly would activate electro-
genic NCX or Na1-K1 pumps. Also, frequency changes
can result in significant alterations in extracellular K1
concentration in the extracellular clefts (843), causing
changes not only in depolarizing but also in repolarizing
transmembrane ionic currents.
On the other hand, other studies suggested that oscil-
lations in the calcium transient amplitude are the primary
alternans driver (851, 853). Such oscillation of calcium
transient can be subsequently translated into APD alter-
nans by NCX and other calcium-sensitive currents.
Calcium-driven alternans was first suggested to origi-
nate from a Ca21 release-reuptake mismatch due to the
steep dependence of Ca21 release on SR loading (851,
854). While in good agreement with a majority of experi-
mental data, the experiments by Picht et al. (855)
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suggested that refractoriness of the ryanodine receptor
rather than release-reuptake mismatch may underlie at
least some of the observed alternans. Such a mecha-
nism is also supported by certain computer models and
may be either due to the refractoriness of the channel or
due to changes in calsequestrin conformations with sub-
sequent RyR block from within the SR (761). In a recent
study utilizing iterated maps as well as a spatially
detailed myocyte model, Qu et al. (856) showed that
both mechanisms may act synergistically to promote
alternans. A third explanation of calcium-driven alter-
nans is the alternans driven by sarcoplasmic reticulum
calcium cycling refractoriness (SRCCR) (857, 858).
SRCCR alternans arises from a combination of steep
load-release relationship (similar to release-reuptake
mismatch hypothesis) and refractoriness of the SR
release (similar to RyR refractoriness hypothesis).
However, the latter does not result from an intrinsic RyR
refractoriness but is a result of a limited rate of refilling
of releasable calcium in the junctional SR. This mecha-
nism underlies alternans in the Rudy-family models (728,
736, 857).
Alternans typically occurs only at rapid heart rates;
however, data from human hearts show that in some
cases alternans manifesting at rapid heart rate may cease
with a further increase in pacing frequency (“eye-type
alternans”) (859). The eye-type pattern was replicated
with a populations-of-models approach (859), with the
mechanism of the eye closure at rapid pacing being
linked to flattening of the SR load-release relationship in
certain conditions (858). Using a spatially distributed
model of calcium handling, Qu et al. (856) also observed
eye-type alternans in simulations where sarcoplasmic
reticulum Ca21-ATPase (SERCA) pumps were
downregulated.
One important question pertaining to the spatial pat-
tern of alternans in tissue is what determines whether
alternans manifests in the relatively benign spatially con-
cordant pattern or the highly proarrhythmic discordant
one. Pastore et al. (849) observed in their experiments
that nodal lines (lines in tissue separating areas of
opposing alternans phase) were associated with struc-
tural abnormalities. However, discordant alternans may
arise even in tissue with no obvious structural abnormal-
ity. Computer models provide two explanations of this
phenomenon. Qu et al. (860) have shown that discord-
ant alternans may emerge as a result of conduction ve-
locity restitution. This explanation is characterized by
the radial pattern of nodal lines with regard to pacing
site. The second explanation by Sato et al. (762) relies
on tissue synchronization of discordant alternans arising
at the subcellular level. This explanation does not rely
on a particular pattern of nodal lines and can explain ex-
perimental observations in Ref. 847.
1125
 VARRÓ ET AL.

FIGURE 20. Short-term temporal variability of repolarization and the risk of sudden cardiac death (SCD). Top left: schematic illustration of QT interval
variability on an electrocardiogram trace. Top right: schematic illustration of action potential duration (APD) variability. Bottom left: increased QT interval
short-term variability in a representative professional soccer player compared with a control individual, illustrated on a Poincare
plot, where each QT
interval n is plotted against its former value, n 1. Bottom right: individual Poincare
plots illustrating increased short-term variability of left ventricular
(LV) monophasic action potential duration (MAPD) in chronic atrioventricular block dogs with SCD compared with control dogs without SCD. (Modified
from Ref. 861 with permission.)

Spontaneous episodes of ventricular tachyarrhythmia densities or functions of transmembrane ion channels

in patients are often preceded by a short-long-short
sequence of cardiac cycles or irregular beat-to-beat vari-
ation of the QT intervals. This temporal instability of
repolarization measured as short-term APD or QT vari-
ability similarly to spatial repolarization inhomogeneity is
considered as an important marker for proarrhythmia
(250, 861) (FIGURE 20). The mechanisms of short-term
APD variability are not fully understood; however, they
may relate to the stochastic behavior of the ion channels
underlying the action potentials or the fluctuation of the
intracellular Ca21 movements and its electrophysiologi-
cal consequences (822).
7. ION CHANNEL AND ACTION POTENTIAL
REMODELING IN ACQUIRED CONDITIONS
Certain diseases and alterations in physiological func-
tions evoke changes in the heart that are collectively
termed remodeling (7). Remodeling can also affect the
and/or pumps, so-called electrical remodeling (TABLE 2)
(7). Thus, electrophysiological remodeling is the result of
changes in the expression of ion channels and pumps,
and it can affect both repolarization and impulse con-
duction. In parallel, remodeling often affects the struc-
ture of cardiac tissue, which can be detected by
microscopy (880). Structural remodeling includes fibro-
sis and wound healing, resulting mainly from the activity
of fibroblasts and myofibroblasts (681, 881, 882). Fibrosis
and scars impair impulse conduction, eliciting conduc-
tion blocks, changing the directions of normal impulse
propagation, and enhancing the heterogeneity of
impulse conduction. Finally, remodeling of the postin-
farction border zone includes alterations to the pattern
and function of gap junctions, further increasing hetero-
geneity of conduction (883). The combined effects of
electrical and structural remodeling increase the pro-
pensity of reentry-based arrhythmias.
In this section, electrical remodeling following from
the best-explored and probably most important

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 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS

Table 2. Remodeling of transmembrane currents/transporters in disease

AF-Atrial Muscle HF-Ventricular Muscle DM-Ventricular Muscle
Current
Reference Reference Reference

INa ; 7 ; 7, 862 ; 863,864

INaL : 126,127

ICa,L ; 7 Ø Ø slow inactiv. 865

Ito ; 7, 549 ; 7, 156, 159, 866 ; 271, 867,868

IK1 : 205 ; 7, 157

IKr ; 7 ;Ø 271, 867, 869

IKs ; 7 ; 271, 867

IKur ;Ø 549, 870

IK,Ach : 358, 584, 871

IKCa (SK2) : 562, 872 : 315, 873 ; 874

If : 788,789, 875,876

NCX : 7, 365

Connexin ; 7 ; 877–879

AF, atrial fibrillation; DM, diabetes mellitus; HF, heart failure; ICa,L, L-type Ca21 current; If, funny/pacemaker current; IK,ACh, acetylcholine-activated potas-
sium current; IKCa, calcium-activated potassium current; IKr, rapid component of delayed rectifier potassium current; IKs, slow component of delayed recti-
fier potassium current; IKur, ultrarapid component of delayed rectifier potassium current; IK1, inward rectifier potassium current; INa, sodium current; INaL,
late sodium current; Ito, transient outward current; NCX, Na1/Ca21 exchanger.

diseases is briefly summarized in order to better under-
stand the mechanisms of cardiac arrhythmias.
7.1. Remodeling in Atrial Fibrillation
AF is the most common sustained arrhythmia in the
developed world, and its prevalence increases with
age, exceeding 10% after the age of 80 yr (6, 884). AF
itself is seldom directly life-threatening and usually
has few acute hemodynamic consequences, but it
represents a high risk for thromboembolism and
stroke given an increased risk of thrombus formation
in the hypodynamic atria (885). It can furthermore con-
tribute to the development of heart failure; therefore
AF has great significance in cardiovascular morbidity
and mortality (886).
Studies performed in atrial tissue originating from
chronic AF patients or experimental animals show sig-
nificantly shorter and often triangular-shaped action
potentials compared with those obtained from sinus
rate patients and animals. It must be emphasized that
data regarding electrophysiological remodeling can
be controversial. For example, in pacing-induced AF in
dog hearts, atrial APD is abbreviated less (1135) than
those observed in human (7, 309). This emphasizes
the importance of the substantial species differences
mentioned above, in this case between dog and
human atrial action potential waveforms (FIGURE 12).
Therefore, the interpretation of results based on ani-
mal experiments should be considered with care in not
only pharmacological but pathophysiological studies
as well.
High atrial rate or tachypacing in experimental animals
induces atrial remodeling (7, 363, 777, 887, 888) that is
characteristic for chronic AF. Atrial extrasystoles or elec-
trical stimulation can easily induce AF in remodeled
atria, and the longer and more often AF episodes are
present, the more pronounced atrial remodeling and vul-
nerability for further AF development become (“AF
begets AF”) (889).
Remodeling in AF is a complex and still not fully eluci-
dated process (7, 30, 34, 887, 890–892). The most well-
established phenomenon in AF is downregulation of L-
type ICa and the corresponding mRNA and proteins. This
occurs irrespective of the underlying cause of AF and is
observed in AF both with and without heart failure. It is

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 VARRÓ ET AL.
considered to be the main cause of APD shortening in
chronic AF. Also, the upregulation of Kir2.1 (the main
channel protein of IK1) and TASK-1 channels has been
reported to contribute to atrial APD shortening in AF
(205). The overall IK,ACh channel (Kir3.1/3.4 1 GIRK)
expression is not significantly changed in chronic AF
(871), but a constitutively active component of this cur-
rent that is very weak in sinus rhythm is greatly
enhanced (358) and is assumed to shorten the APD in
AF. A very recent study also indicated that cholinergic
M1 receptors were upregulated, further activating IK,ACh
and thereby shortening atrial repolarization (871). Both
downregulation (549, 870) and no change of IKur have
been observed in chronic AF. A recent study in a tachy-
paced dog AF model (562) confirmed the expression
changes of SK2 or SK3 channels, which supported the
results of an earlier study (872) in mice. Ito is downregu-
lated in chronic AF (7, 549), which is well reflected in the
widening of early atrial repolarization of AF and its
increased AP duration at 20% repolarization (APD20)
Intracellular Ca21 handling is impaired in chronic AF
associated with heart failure (893), as increased open
probability of the ryanodine receptor SR channels
results in more frequent Ca21 release from the intracel-
lular Ca21 store (681, 824, 887). This may subsequently
enhance the frequency of spontaneous depolarization
in AF via NCX, possibly contributing to the increased
triggered activity in chronic AF (803).
Structural remodeling has been observed in a tachy-
paced AF goat model (880), which seems even more
pronounced in AF associated with heart failure (894).
This includes elevated levels of fibrosis (34) and other
extracellular matrix components such as myofibroblasts,
periostin, matrix metalloproteinases (MMPs), and trans-
forming growth factor b1 (TFG-b1). Kidney disease (895),
inflammation (29), and oxidative stress (896, 897) were
also associated with arrhythmogenesis and remodeling
in AF. Several reports proved the important role of cal-
modulin-dependent protein kinase II (CaMKII) in both
abnormal Ca21 handling and structural remodeling in
AF, suggesting CaMKII inhibition as a promising new
strategy to treat AF (573, 898, 899).
7.2. Remodeling in Heart Failure
Sudden cardiac death caused by arrhythmias (900) is re-
sponsible for a substantial proportion of the mortality in
heart failure. The overwhelming majority of published
papers confirmed significant lengthening of repolariza-
tion of the ventricular muscle without substantial species
differences and regardless of its origin. This is also asso-
ciated with increased dispersion of repolarization (241),
which can be further enhanced by bradycardia-induced
AP prolongation often seen in this situation. Enhanced
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fibroblast/myofibroblast activity, fibrosis, and altered
connexin expression (877, 879) impair impulse con-
duction (881) and contribute to impulse propagation het-
erogeneity (901, 902). These changes alone and in com-
bination with heterogeneity of repolarization (25, 903)
would result in a favorable substrate for reentry arrhyth-
mias (FIGURE 2). An additional source of proarrhythmic
substrate is the high vulnerability of failing hearts to
repolarization alternans (846, 904), which appears to
result mainly from remodeling of calcium handling. For
example, Nivala et al. (905) utilized a detailed model of
spatiotemporal calcium handling to investigate the con-
sequences of heart failure remodeling. They have
shown complex interactions of disruption of T tubules
together with SERCA downregulation to promote
increased alternans vulnerability. A different theoretical
study also highlighted the importance of SR calcium
release dynamics and how their changes in heart failure
promote alternans (858).
The ionic mechanisms underlying electrophysio-
logical remodeling in the ventricle include downregu-
lation of Kv4.3 channels and Ito, Kir2 channels and IK1,
SK2 channels, KvLQT1 channels, and IKs (156–159,
866, 873). Peak INa can be reduced in failing heart by
posttranscriptional reduction and deficient glycosyla-
tion of Nav1.5 channel a-subunit (862), and these
changes may contribute to slowing of impulse and
conduction. In a mouse transverse aortic constriction
HF model, Nav1.5 remodeling was observed in sub-
cellular microdomains: Nav1.5 cluster size at the lat-
eral membrane and at the intercalated disk was
reduced in failing myocytes, in agreement with
reduced peak INa and impaired transversal and longi-
tudinal conduction in failing myocardium (98). More
importantly, late INa is significantly increased both in
an experimental heart failure model (127) and in
patients (126); the substantial inward current during
the plateau phase causes failure of repolarization
and decreases its homogeneity, providing substrate
for reentry arrhythmias. In rabbit and human ventricular
muscle, downregulation and change of the transmural
expression pattern of CFTR Cl channels was observed
(906) in the hypertrophied heart. Connexin 43 protein
downregulation and its lateralization delay impulse con-
duction and can enhance anisotropic impulse propaga-
tion (878), further contributing to substrate generation
for arrhythmias.
In addition to remodeling of ionic channels, cal-
cium handling is substantially altered, showing
increased SR leak and reduced SR reuptake, result-
ing in low SR calcium loading and thus diminished
calcium transient (802). An additional factor contrib-
uting to low SR loading and calcium transient is the
increased NCX (907). The alterations of calcium
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
handling affect the SR-mitochondria cross talk, lead-
ing to energy starvation of failing cells, affecting
energy-sensitive processes (908). CaMKII signaling
is also strongly affected, with relevance for arrhyth-
mia formation (802).
Changes in electrophysiology and calcium handling in
heart failure promote ectopic automaticity in the PVs,
atria, and ventricle, serving as an important trigger for
reentry arrhythmias (788, 790, 875, 909, 910). One type
of automaticity may arise from pacemaker-like currents
in ventricles. The pacemaker HCN4 and HCN2 channels
that carry the If inward pacemaker current have been
reported to be upregulated in ventricular (788, 789, 875,
876, 911) and atrial (912) tissue of heart failure patients. In
contrast, downregulation of If in the SAN has also been
observed (913). A second type of automaticity may arise
from afterdepolarizations resulting from increased cal-
cium leak and subsequent spontaneous SR release, to-
gether with the upregulated NCX (907). This increased
risk of DADs is further enhanced by the above-men-
tioned reduction in IK1 (291), which makes it easier for the
depolarization to reach the threshold of INa reactivation.
More importantly, heart failure alters cellular Ca21 han-
dling (681, 914). Calcium leak from the SR is enhanced,
resulting in spontaneous Ca21 release from the SR
(802, 824, 915). This transient intracellular Ca21 concen-
tration increase activates the already upregulated (907)
forward NCX, leading to arrhythmogenic depolarizations
serving as triggers in an environment where the sub-
strate also favors the development of arrhythmias due
to heterogeneity of impulse conduction and repolariza-
tion. In this process, CaMKII seems to have an important
role since its inhibition can have beneficial antiarrhyth-
mic consequences (802).
7.3. Remodeling in Hypertrophic Cardiomyopathy
and in Athlete’s Heart
Hypertrophic cardiomyopathy (HCM) was first described
in 1958 after autopsies on individuals who suffered
unexpected sudden cardiac death (916). Since then,
HCM has been identified as the most common inherited
heart disease, with a prevalence of 1:500 (917), caused
by >1,400 known mutations in at least 11 genes (most
commonly in b-myosin heavy chain, MYH7 and myosin
binding protein C, MYBPC3 genes) encoding different
sarcomeric and Z-disk proteins (243). The disease is
characterized by variable left ventricular hypertrophy
and fibrosis (918) and increased incidence of serious
ventricular arrhythmias (919, 920). Moreover, HCM is the
most common cause of SCD in young persons and com-
petitive athletes under the age of 35 yr (919, 921). The
increased propensity for ventricular arrhythmia develop-
ment in patients with HCM is mainly attributed to
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structural left ventricular remodeling (922). Indeed, dis-
organized myocyte architecture (923), intramyocardial
and replacement fibrosis, and collagen deposition in
regions with chronic microvascular ischemia (924) can
serve as substrates for sustained arrhythmias (925). In
addition, the surrounding ischemic myocardium mani-
fests impaired conduction and heterogenous repolariza-
tion dispersion in advanced stages of HCM (926).
Alternans is another source of proarrhythmic substrate
in HCM (927). However, most SCD events occur in HCM
patients at early disease progression stages, when left
ventricular hypertrophy is the only major structural ab-
normality (928). Accordingly, several key elements and
consequences of electrical remodeling have been iden-
tified in cardiomyocytes from HCM patients, including
more frequent EAD and DAD formation (160), increased
diastolic Ca21 concentration and elevated NCX expres-
sion (160), and increased left ventricular HCN4 expres-
sion (792), all capable of providing arrhythmia triggers in
HCM (27, 929, 930). In addition, prolongation of the
APD (160) and, consequently, QTc lengthening were
observed in patients with HCM, which can be caused by
the reduced densities of Ito and IK1, decreased expres-
sions of hERG1b and KCNQ1, and increased INaLate and
slower ICa,L inactivation kinetics (160, 931) in myocytes
from HCM patients. These elements of ionic current
remodeling were sufficient to recapitulate increased vul-
nerability to EADs when incorporated into a ventricular
myocyte model (776).
In competitive athletes, chronic endurance training
leads to the development of the so-called athlete’s
heart, characterized by lower resting heart rate due to
increased vagal tone (932), If downregulation (933), and
symmetric cardiac hypertrophy (934). The incidence of
sudden cardiac death in top competitive athletes is two
to four times higher compared with the age-matched
population (935). Interestingly, hypertrophic cardiomy-
opathy is found in almost 40% of the cases of SCD in
athletes (919). The electrophysiological mechanisms
underlying SCD in athletes are not known (for a review
see Ref. 18); nevertheless, a significantly larger short-
term variability of the QT interval was found in professio-
nal soccer players, indicating increased repolarization
temporal instability (936) that can refer to increased ar-
rhythmia susceptibility in this population (259, 937).
7.4. Remodeling in Diabetes Mellitus
Diabetes mellitus represents a significant burden on
health care systems all over the world since its preva-
lence is continuously increasing. Diabetes mellitus, an
endocrine disorder, is characterized by reduced insulin
production (type 1) or increased insulin resistance (type
2), with the latter belonging to cardiometabolic disorders
1129
 VARRÓ ET AL.
and being responsible for 90% of diabetes mellitus
cases. Cardiac repolarization disturbances like QTc
lengthening or increased QT dispersion are associated
with the disease, and cardiovascular complications
including arrhythmias and sudden death are major
causes of mortality and morbidity in diabetes. These
complications usually develop slowly over several deca-
des and are associated with cardiomyopathy, ischemia,
vascular sclerosis, and neuropathy with complex and
not fully understood mechanisms. Here, we briefly
summarize those electrophysiological and structural
changes that can be attributed directly to diabetes-
induced remodeling (938). The majority of the available
data regarding electrical remodeling are derived from
type 1 diabetes animal models. There, diabetes is
induced acutely by alloxan or streptozotocin (raising the
question of how well the model corresponds to chronic
changes developing slowly over decades in humans).
Results in type 1 diabetes animal models include length-
ening of ventricular repolarization, attributed to down-
regulation of Ito (868) and IKs currents. At the level of
mRNA and protein, Kv4.2, Kv4.3, and minK were reduced
but Kv1.4 and KvLQT1 did not change or were upregu-
lated. Zhang et al. (869, 939) reported significant length-
ening of QTc and downregulation of cardiac HERG
channels and IKr in alloxan-induced type 1 rabbit diabe-
tes; however, the latter results regarding IKr were not
confirmed by other studies in rabbits and dogs (271,
867). In Goto–Kakizaki type 2 diabetic rats, ICa,L and
Ca21 transient did not change compared with those in
the control animals but decreased atrial KCNN2 mRNA,
KCa2.2 protein levels, and corresponding SK2 current
densities were observed (874, 940), with concomitantly
enhanced myocardial hypertrophy and extracellular ma-
trix deposition with fibrosis (941). In Zucker rats, another
type 2 diabetic model, enhanced fibrosis, Cx43 laterali-
zation, and significant APD prolongation with delayed
ICa,L inactivation (942) were observed (865). Another ob-
servation in type 1 and 2 rat diabetes models is the
reduced impulse conduction reserve (863, 943). In a
recent paper, O-GIcNAcylation and impaired function of
Nav1.5 channel (864) and INa were described, which to-
gether with the fibrotic structural changes (944) can also
contribute to the arrhythmogenic impulse conduction
defects (945).
In addition to changes in ionic channels, calcium han-
dling is also altered. Several experimental studies in
both type 1 and 2 diabetes models in rat established
increased SR Ca21 leak due to enhanced RyR2 channel
activity (946, 947), which, as mentioned above, would
be expected to result in DADs and extrasystoles.
Accordingly, Yaras et al. (948) showed increases in
Ca21 spark frequency in cardiomyocytes from RYR2
and decrease in FKBP12.6 (calstabin) association. Also,
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enhanced CaMKII-mediated phosphorylation of RyR2
has been linked to aberrant Ca21 handling in the same
animal model (949, 950). Although it is less well estab-
lished, similar pathophysiological alterations have been
observed in type 2 diabetic rats (951, 952). Results
obtained from experimental diabetes suggest that the
diabetic heart provides favorable substrate and inc-
reased propensity of trigger for arrhythmias due to
enhanced ectopic activity and both impaired impulse
conduction and repolarization, but results are not con-
clusive. Therefore, further studies with more appropriate
experimental diabetes models are needed to better
understand the mechanisms of arrhythmias in diabetes
mellitus.
7.5. Myocardial Ischemia, Infarction, and
Arrhythmias
Myocardial ischemia mostly develops on the basis of
coronary artery disease following critical decreases in
blood flow in obstructed coronary arteries. Occlusion of
coronary arteries induces a chain of events within
minutes of the onset of ischemia, leading to altered func-
tion of ion channels and concomitant ischemia- and in-
farction-induced cardiac arrhythmias. The majority of
cases where ventricular tachyarrhythmias including ven-
tricular fibrillation lead to sudden cardiac death are
clearly associated with coronary artery disease and
myocardial infarction (953, 954). Reperfusion of the
myocardium is necessary for tissue survival; however, it
can also lead to reperfusion-induced arrhythmias (955,
956). When timely revascularization is not performed,
coronary obstruction leads to irreversible cell damage
termed myocardial infarction, and the dead cardiomyo-
cytes are replaced by scar tissue. The remodeling in sur-
viving epicardial and border zone myocytes mostly
leads to conduction abnormalities, while surviving endo-
cardial Purkinje fibers can be important sources of trig-
gered activity (618). In addition, over the course of days
and weeks, the noninfarcted myocardium, including the
peri-infarct border zone, also undergoes significant
remodeling that favors arrhythmia development due to
changes in conduction, refractoriness, and triggered ac-
tivity (31). An additional source of increased dispersion
of refractoriness is the vulnerability of the infarct border
zone to alternans, shown both computationally (847)
and experimentally (847). Such spatially localized alter-
nans is proarrhythmic in a fashion similar to spatially
discordant alternans, forming steep gradients of repola-
rization. Multiple other studies have investigated arrhyth-
mia mechanisms associated with myocardial ischemia
and infarction; for comprehensive detailed reviews, the
reader is referred to works by Janse and Wit (31) and
Pinto and Boyden (784).
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
In the acute phase of myocardial ischemia (within
minutes to 2–4 h after coronary blood flow reduction),
ventricular arrhythmias including fibrillation occur in
humans (957) and also in experimental animals sub-
jected to complete coronary artery occlusion (958, 959).
Acute ischemia promotes the formation of arrhythmia
substrate, which allows reentry via several mechanisms.
The resting membrane potential of ischemic cardiomyo-
cytes is significantly depolarized (960), partly due to
marked K1 loss and intracellular acidosis (783), leading
to extracellular K1 accumulation in ischemic tissue (961).
The depolarization of the resting membrane potential
depresses action potential upstroke and amplitude by
reducing INa and results in the prolongation of the refrac-
tory period via slow recovery from inactivation of the so-
dium gates (39). Activation of ATP-dependent potassium
channels shortens the action potential duration (962).
Within 15 min of the onset of ischemia, gap junction
channel phosphorylation status is changed and they get
translocated into intracellular pools in ischemic cells
(963), severely reducing cell-to-cell coupling (815, 964,
965). These changes result in impaired impulse conduc-
tion in acute ischemia (966). Increased spatial dispersion
of repolarization and refractoriness between different
regions of the myocardium is also an important arrhyth-
mia substrate (128). Nonuniform shortening of the action
potential due to heterogeneous sarcolemmal IK,ATP acti-
vation in myocytes from the ischemic and border zone
(reviewed in Ref. 967) and no shortening of AP in the
normoxic myocardium increases dispersion of repolari-
zation and effective refractory period within minutes af-
ter ischemia onset (340). The first phase of ventricular
arrhythmias (“phase 1a”) peaking between 5 and 6 min
after the onset of ischemia in experimental models is
usually, but not exclusively, attributed to the mecha-
nisms described above (31, 968), which have been fur-
ther investigated in computer simulation studies using
human biventricular models (969).
Multiple mechanisms underlie the formation of ar-
rhythmia triggers in acute ischemia. The increased
release of catecholamines occurs 15–20 min after the
onset of myocardial ischemia (970), possibly increasing
ectopic activity. Early and delayed afterdepolarizations
can supply the triggers for arrhythmia initiation in acute
myocardial ischemia. Early afterdepolarizations can de-
velop in Purkinje fibers in acute ischemia because of in-
tracellular acidosis and exposure to ischemia-induced
release of lysophosphatidylcholine (971). Delayed after-
depolarizations can occur in ischemic cells because of
acidosis, hypoxia, and calcium overload (617). A so-
called “injury current” flowing from ischemic myocar-
dium to normal myocardium can cause increased abnor-
mal automaticity in acute myocardial ischemia. The
basis for this current is the difference in membrane
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potentials between neighboring ischemic (depolari-
zed) and normoxic (hyperpolarized) myocardium and
has been shown to contribute to ectopic activity in ex-
perimental conditions (972–974) and computer simu-
lations (706). In general, the initiation of so-called
“phase 1b” arrhythmias in experimental models of
myocardial ischemia is mostly attributed to increased
automaticity (31).
In the subacute and chronic phases of myocardial in-
farction, reentry and triggered activity caused by early
and delayed afterdepolarizations are major mecha-
nisms of infarction-induced ventricular arrhythmias
(28, 975), where surviving Purkinje fibers (976) and epi-
cardial border zone myocytes (977) play a critical role
in arrhythmia development. A series of papers by the
Boyden group describe the morphological and electro-
physiological changes occurring over 24–48 h after an
infarction in surviving left ventricular Purkinje cells that
underlie subacute spontaneous arrhythmias (for a
detailed review, see Ref. 784). In general, surviving
Purkinje fibers exhibit depolarized resting potentials
associated with reduced IK1 (978), decreased ICa,L and
ICa,T densities (979), prolonged repolarization with up
to 51% smaller Ito density, and delayed Ito reactivation
kinetics (980). Also obs-erved were nonuniform cal-
cium transients and abnormal calcium waves leading
to spontaneous action potentials and triggered activity
in the infarcted heart (619). The surviving epicardial
myocytes of the border zone next to the infarcted area
exhibit decreased excitability and resting potential,
reduced upstroke velocity and amplitude of the action
potential (977), and, importantly, marked postrepolari-
zation refractoriness (32, 981) due to decreased INa
density and altered INa kinetics (982). A pathological
redistribution of connexin 43 gap junction protein and
reduced gap junctional conductance was observed in
border zone surviving cardiomyocytes (983). These
changes lead to abnormal, slow, and anisotropic
impulse conduction (28, 984, 985). Interestingly, in
these surviving epicardial myocytes, a gradual short-
ening and triangularization of the action potential was
observed over 2 wk, followed by a return of action
potential parameters to normal by 2 mo after myocar-
dial infarction (986). The reduced ICa,L density (987)
may be partly responsible for the triangularization of
the action potentials on these cells. Several important
repolarizing K1 currents are downregulated in surviv-
ing epicardial cells, including Ito (977) and IKr and IKs
(240), leading to prolonged action potentials. These
changes described above in epicardial border zone
myocytes strongly favor the development of reentry
and, of particular interest, anisotropic reentry (7).
In addition to the changes described above, the
remote noninfarcted regions of the myocardium also
1131
 VARRÓ ET AL.
exhibit structural and electrical remodeling as the
remaining myocardium in the infarcted heart adapts to
increased workload (988) The developing regional left
ventricular hypertrophy is an important risk factor for the
generation of severe ventricular arrhythmias (989) and
probably relates to enhanced dispersion of repolariza-
tion associated with myocardial hypertrophy.
7.6. Aging-Associated Cardiac Remodeling
There is a dramatic increase in the incidence and preva-
lence of cardiovascular disease and mortality with age,
and aging is now identified as a major risk factor for cardi-
ovascular morbidity (990). Evidence suggests that cardio-
vascular aging is associated with remodeling of the heart,
setting the stage for arrhythmia development (especially
atrial fibrillation and ventricular tachycardia) and reduced
cardiac function. The incidence of sudden cardiac death
increases with age (991); however, our understanding of
the mechanisms responsible for increased incidence of
arrhythmias in the elderly remains limited (992). Many of
the aging-associated alterations are, at least in part, inevi-
tably due to the observed coronary artery dysfunction,
increased artery stiffness, decreased responsiveness to
b-adrenergic stimulation, and cardiac extracellular matrix
remodeling found in the elderly (993–995).
The pacemaker function of the sinus node signifi-
cantly decreases in older patients, probably because of
replacement of pacemaker cells within the sinoatrial
node (SAN) by extracellular matrix (996). Animal studies
suggest that decreased expression of HCN2, ICa,L, ICa,T,
and Kv1.5 channels can also contribute (548, 997, 998).
Consequently, the rate of spontaneous diastolic depola-
rization falls and action potential duration is prolonged
in pacemaker cells (523, 999). The intrinsic heart rate
decreases (997), with concomitant fatigue, bradycardia,
and increased incidence of supraventricular arrhythmias
including atrial fibrillation in the elderly (1000).
The observed delayed and impaired cardiac impulse
conduction, with concomitant QRS complex widening, is
the result of decreased Cx43 expression and degenera-
tive changes in the cardiac connective tissue (992,
1001–1003).
In aged ventricles, even without the presence of struc-
tural heart disease, loss of cardiomyocytes, reactive hy-
pertrophy in the left ventricle, fibrosis, and changes in
repolarization occur (161, 1004–1006). The prolongation
of the ventricular action potential was observed in sen-
escent sheep (1007), and consequent QT interval length-
ening was shown in old dogs (1007, 1008). In an attempt
to maintain cardiac function, ion channel remodeling
involving ICa,L, Ito, KATP expression changes, delayed ICa,L
inactivation, and increased INa,late are probably
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responsible for repolarization prolongation in aged
hearts (1009, 1010). These elements of ventricular
remodeling in the aged heart increase susceptibility to-
ward arrhythmias by altering cellular coupling, increasing
anisotropic conduction, and enhancing heterogeneity of
refractoriness in the myocardium, which are changes
that all together favor reentry initiation and stabilization.
The increased expression of NCX, the delayed inactiva-
tion of ICa,L, together with reduced expression of SERCA
and other proteins related to calcium handling all con-
tribute to impaired calcium homeostasis and provide the
mechanisms for increased triggered activity in the aging
myocardium (1011–1015).
The ability of the heart to properly respond to auto-
nomic stimuli also decreases with aging (1016). Red-
uced b-adrenoceptor responses and receptor den-
sities were identified in the aging myocardium (1017,
1018), exacerbated by decreased cAMP production
(995). It is not clear how impaired cAMP-dependent
regulation of IKs (1019) and ICa,L (1020) translates into
alterations of repolarization reserve in the elderly. In
addition, decreased vagal component of heart rate
variability and heart rate responses were observed af-
ter muscarinic acetylcholine receptor blockade (1021,
1022). The impaired autonomic regulation of the heart
and the electrical and structural remodeling described
above in the elderly contribute to reduced cardiac
adaptive responses and increased supraventricular
and ventricular arrhythmia susceptibility (1023).
8. INHERITED CONDITIONS ASSOCIATED
WITH ION CHANNEL DYSFUNCTION
Cardiac arrhythmias are usually symptoms or consequen-
ces of other underlying diseases such as myocardial is-
chemia or infarction, heart failure, hypertension, diabetes,
etc. However, cardiac ion channel mutations or polymor-
phisms (1024) can represent the primary cause of arrhyth-
mias, collectively called “ion channelopathies” (1025).
This field is particularly rapidly expanding, and detailed
discussion is far beyond the scope of this review; some
excellent recent reviews are suggested for further read-
ing (114–117, 149, 246, 1026–1029).
In general, mutation of a certain ion channel can
cause gain or loss of function (1029–1032) resulting in
increased or decreased current through the affected ion
channel, which may alter arrhythmia trigger and/or sub-
strate (TABLE 1) (245, 1033, 1034).
Congenital LQT syndrome is characterized by prolon-
gation of myocardial AP and QT interval caused by the
reduction of repolarizing current due to either loss-of-
function mutations in repolarizing current-conducting
potassium channels or gain-of-function mutations in
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
depolarizing current-conducting sodium or calcium
channels (114, 115) (TABLE 1). Congenital LQT syndrome
is commonly associated with the development of TdP
and sudden cardiac death (1035), and most LQT syn-
drome subtypes show an autosomal dominant inheri-
tance (115). In >90% of patients with congenital LQT,
genetic variants of KCNQ1 encoding the a-subunit Kv7.1
of IKs (LQT1; 30–35% of cases), KCNH2 encoding the
a-subunit Kv11.1 of IKr (LQT2; 25–40% of cases), and
SCN5A encoding the a-subunit Nav1.5 for INa (LQT3; 5–
10% of cases) underlie the disorder (122, 1036, 1037)
(TABLE 1). A number of other genes encoding ion chan-
nel proteins or their regulators have been implicated as
causes of congenital LQT syndrome (TABLE 1). For
details on the causative roles of the genetic variants
involved in the different congenital LQT syndrome sub-
types, the reader is referred to other comprehensive
reviews (115, 246). In LQT syndrome, prolongation of
repolarization and refractoriness, accompanied with
increased dispersion of repolarization (1038, 1039),
enhance the substrate for typical ventricular arrhythmias
in patients with LQT syndrome such as TdP polymorphic
tachycardia and ventricular fibrillation. Enhanced trig-
gered activity due to early afterdepolarizations, elicited
by reactivation of ICa,L during the prolonged AP, provides
the trigger for the development of TdP in LQT syndrome
(796, 1038). LQT syndrome is characterized by incom-
plete penetrance and can be “silent,” i.e., no significant
prolongation of repolarization and QT interval is
observed. However, congenital LQT syndrome greatly
enhances the effect of any other factor which delays
repolarization by other mechanisms. This can be
explained by the concept of “repolarization reserve,” as
introduced in sect. 3.4.2 (228, 257, 1040, 1041).
Accordingly, impaired function of different types of po-
tassium channels (caused by genetic mutation, disease-
induced downregulation, or drug effects) can add to-
gether, further enhancing the substrate for ventricular
arrhythmias. Of note, ion channel polymorphisms can
also play a role in arrhythmia development, thus empha-
sizing the importance of pharmacogenetics during the
evaluation of proarrhythmic drug-induced adverse
effects (798, 1024). Which current is affected by such
polymorphisms (usually potassium currents, ICaL, or
INaLate), may largely determine the individual’s response
to antiarrhythmic channel-blocking drugs, emphasizing
the concept of personalized med-icine.
SQT syndrome (1042, 1043) is a rare, albeit severe, chan-
nelopathy that is characterized by abnormally short fre-
quency-corrected QT intervals (<360 ms), due to
accelerated ventricular repolarization (1044), with a high
risk of sudden cardiac death and AF (1045). SQT syndrome
shows autosomal dominant inheritance, and gain-of-func-
tion mutations in genes encoding different potassium
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channels, i.e., KCNH2 (SQT1), KCNQ1 (SQT2), and KCNJ2
(SQT3), have been associated with the disorder (1046–
1048) (TABLE 1). In addition, loss-of-function mutations in
genes encoding voltage-gated calcium channel subunits
CACNA1C, CACNB2b, and CACNA2D1 were designated
as SQT4, SQT5, and SQT6, respectively (1049) (TABLE 1).
Patients with SQT syndrome involving calcium channel
mutations exhibit an overlapping phenotype combining
short QT and a Brugada syndrome phenotype (1050).
Loss-of-function mutations in the gene (SLC22A5) encod-
ing a sodium-dependent carnitine transporter have been
termed SQT7 (1051) (TABLE 1). In SQT7, the mechanistic
link between short QT and carnitine concentrations
remains elusive; however, increased IKr due to the lack of
long-chain acylcarnitines may play a role (1052). SQT8 syn-
drome involves a mutation in the gene (SLC4A3) encoding
a Cl /HCO3 exchanger (AE3) leading to a trafficking defect
of the mutated AE3 to the cell membrane (1053) (TABLE 1).
The shortening of APD and ERP in the myocardium, as well
as the increased spatial dispersion of repolarization, due to
more enhanced APD shortening in the epicardium, all favor
reentry tachycardia development both in the ventricles and
in the atria in SQT syndrome (1054, 1055).
Brugada syndrome (BrS) (1056) and arrhythmogenic
right ventricular cardiomyopathy (ARVC) (1057) are
inherited cardiac diseases with a complex genetic back-
ground. Brugada syndrome is characterized by ST seg-
ment elevation in right precordial leads and has been
considered as the cause of SCD in up to 20% of patients
with a structurally normal heart (778). Approximately 20–
30% of patients with BrS exhibit pathogenic mutations in
the SCN5A gene encoding the a pore-forming subunit
of the cardiac Nav1.5 sodium channel (1058), leading to
loss of function in fast INa and, consequently, conduction
slowing and delayed right ventricular activation (1059,
1060). In BrS, because of decreased INa the balance of
outward and inward currents changes and the repolariz-
ing effect of Ito is amplified in epicardial but not in endo-
cardial cells, resulting in enhanced transmural dis-
persion of repolarization. This increased dispersion can
create a vulnerable window for extrasystoles to induce
phase 2 reentry arrhythmias (1061, 1062). In a genome-
wide association study, genetic variants of SCN10A-
encoded Nav1.8 sodium channels, playing a key role in
cardiac neurons (1063) but also expressed in the work-
ing myocardium (1064), have been identified as strong
modulators for BrS (1065). In addition, in 2–5% of BrS
patients pathogenic variants have been identified in a
number of genes encoding other ion channel proteins,
and up to 70% of patients with BrS have an unidentified
genetic cause (778, 1058). Interestingly, the expression
of Kv4.3, a key subunit of Ito (135), was markedly reduced
in the endocardium but not in the epicardium in patients
with BrS (1066). This enhanced transmural difference in
1133
 VARRÓ ET AL.
Ito can lead to increased transmural dispersion of repola-
rization in BrS patients, favoring the development of
reentry arrhythmias (24, 1062).
In patients with ARVC, a significant number of cardio-
myocytes in patches of the right ventricular free wall are
replaced by fibroadipose tissue, with marked patho-
physiological consequences for myocardial depolariza-
tion and repolarization of the right ventricle (1057). The
causative role of mutations in at least 16 genes, mostly
encoding different desmosomal proteins, has been
identified in ARVC (1067), whereas in 40–50% of
patients the genetic cause is unknown (1068). The exact
molecular mechanisms for how desmosome assembly
impairment and dysfunction lead to cardiomyocyte apo-
ptosis and their fibroadipose replacement are not fully
understood (1069, 1070). ARVC is associated with fre-
quent ventricular extrasystoles, ventricular tachycardia
with left bundle branch block morphology, syncope, and
SCD (1071). On autopsy, ARVC is found to be responsible
for SCD in 5% of young competitive athletes in the
United States, whereas this number is around 27% in
northern Italy (1072, 1073). The fibroadipose tissue
patches correspond to electroanatomical scars that pro-
mote the establishment of scar-related macro reentry
circuits (1074, 1075).
Catecholaminergic polymorphic ventricular tachycar-
dia (CPVT) is characterized by a normal resting ECG;
however, malignant ventricular arrhythmias and SCD are
induced by adrenergic stimulation (821, 1076). Mutations
in RYR2, encoding the ryanodine receptor 2, the Ca21
release channel located on the SR (autosomal dominant
CPVT type 1), and in CASQ2, encoding calsequestrin 2,
the calcium binding protein inside the SR (autosomal re-
cessive CPVT type 2), makes these channels and cal-
cium storage sites more sensitive to catecholamine-
induced Ca21 release (1077). Consequently, spontane-
ous triggered automaticity is induced by depolarizations
due to increased transient inward current elicited by for-
ward NCX activity during diastole. Iyer et al. (1078) used
computer simulations to characterize the impact of
RYR2 and calsequestrin mutations in the CPVT pheno-
type. Their study shows how impaired SR calcium sens-
ing and increased spontaneous SR calcium release
promote DADs and how these events are aggravated
by b-adrenergic stimulation.
Mutations in If pacemaker channels can cause both
brady- and tachycardias (1034) by altering sinus automa-
ticity. Sinus bradycardia was also reported in patients
with loss-of-function mutation of the SCN5A sodium
channels resulting in failure of pacemaker capture
(1079). Some familial AF cases are also linked to different
ion channel mutations in the atria, influencing repolariza-
tion, depolarization, connexin function, and conse-
quently impulse conduction properties (1080).
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9. OTHER FACTORS INFLUENCING
ARRHYTHMOGENESIS
9.1. Sex Differences in Cardiac Electrophysiology
and Arrhythmias
Sex differences in cardiac electrophysiology carry
marked clinical significance because they translate into
distinct arrhythmia risks and outcome in men and women.
Although women have a somewhat smaller risk of AF or
ventricular fibrillation (VF) compared with men (1081), this
does not hold for all causes of arrhythmia. For example,
women have a longer frequency-corrected QT interval
and are more susceptible to development of drug-
induced polymorphic ventricular tachycardia (1082–
1085), whereas men are more likely to exhibit early repo-
larization (150). Here we briefly discuss the underlying
mechanisms for sex differences in cardiac electrophysiol-
ogy; for more detailed discussions the reader is directed
to recent comprehensive reviews (265, 1081).
Sex hormones exert their effects via both transcrip-
tional regulation (1086, 1087) and acute, nongenomic
modulation of intracellular signaling (1088). Women ex-
hibit greater sinoatrial node automaticity (1089), and
pregnancy increases pacemaker If current density along
with HCN2 expression in mice (1090). A larger INaLate
was observed in male rabbit left atrial posterior wall
myocytes (1091). Since these cells are major sources of
non-pulmonary vein triggered activity (204, 1092), and
INaLate is an important contributor in atrial arrhythmogen-
esis (1093), the larger INaLate may contribute to higher
triggered activity in males, leading to the initiation of AF.
The prolonged ventricular repolarization in women is
partly due to decreased expression of pore-forming
and/or auxiliary subunits of ion channels carrying repola-
rizing currents, including Ito, IK1, IKr, IKs, and KATP in
humans (151), and these results are generally in agree-
ment with animal studies showing lower densities for
these currents (263, 1094–1096). In addition, 17b-estra-
diol (E2) directly (nongenomic effect) reduces IKr and
enhances IKr block and QTc prolongation by HERG
blocker drugs (1085, 1097), whereas testosterone
increases IKr and IKs (1094, 1098) and progesterone
enhances IKs (1099). Indeed, the normalization of the
QTc interval in a woman with long QT syndrome was
observed during pregnancy due to increased progester-
one levels (1100). A greater transmural IKs density gradi-
ent was found in female dogs compared with males
(1101), possibly contributing to larger transmural APD het-
erogeneity in females. Opposite effects of b-adrenergic
stimulation by isoproterenol on Purkinje fiber APD were
observed in male dogs (APD shortening) compared with
female dogs (APD prolongation), highlighting sex- and
age-related differences in the autonomic regulation of
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
the cAMP-dependent IKs current (1102, 1103). Since IKs is
a key current for repolarization reserve (228, 250, 260),
these changes may lead to reduced repolarization
reserve and an increased arrhythmia substrate in
women.
A more heterogeneous transmural INa distribution was
found in female canine left ventricle (1104), and testoster-
one increased epicardial INa amplitude in female dogs to
levels similar to those measured in male epicardium
(1104). As INa and Ito have opposing effects on repolariza-
tion, increased transmural heterogeneity in ion channel
expression creates transmural dispersion of repolariza-
tion that serves as an arrhythmogenic substrate (128).
Sex-dependent differences in ICa,L densities and Ca21
homeostasis protein expression and regulation (162)
lead to sex differences in triggered activity, since the
reactivation of the L-type calcium current during the pla-
teau of the action potential and Ca21 cycling protein
dysfunction importantly contribute to EAD formation (10).
Larger ICa,L densities were found in all transmural layers
of the left ventricle in female dogs (1101), possibly con-
tributing to a bigger transmural heterogeneity of APD in
females, since IKs (similar in male and female midmyocar-
dium) could not offset the increased ICa,L. In addition, es-
tradiol increased ICa,L (1105) and promoted EAD
formation and sudden cardiac death in rabbits with
LQT2 syndrome (1106), whereas testosterone and pro-
gesterone exerted opposite effects (1088, 1106, 1107). In
female rabbit left ventricle, NCX expression and current
were higher, resulting in increased EAD development
following the administration of the HERG blocker dofeti-
lide (1108). Testosterone, however, increased SERCA
function, causing rapid removal of excess intracellular
Ca21 (1109). Testosterone increased RyR2 activity (1109),
whereas estradiol increased RyR2 leakiness and con-
tributed to the formation of proarrhythmic afterdepolari-
zations (1110). A significantly lower expression of Cx43
was found in left ventricular myocardium in women com-
pared with men (151) that can make women more sus-
ceptible to ventricular conduction impairment.
In summary, sex hormones significantly modulate
both the arrhythmia substrate and triggered activity
leading to sex differences in ECG morphology and sus-
ceptibility to supraventricular and ventricular arrhyth-
mias. Estradiol lengthens repolarization, promotes EAD
formation, and exacerbates the QT-prolonging effect of
HERG blocker drugs, leading to higher incidence of car-
diac arrhythmias in females, whereas testosterone and
progesterone exert mostly opposite effects.
9.2. Serum Ion Concentration Changes
Potassium is by far the most important ion in blood that
affects arrhythmogenesis (233, 1111–1113). As mentioned
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above, extracellular K1 concentration significantly mod-
ulates several K1 currents (225, 233–235, 294, 1114) in
the range of blood K1 concentrations (2–10 mM)
observed frequently in clinical practice. Hyperkalemia
depolarizes the cell, as expected from the Nernst equa-
tion. The depolarization caused by elevated extracellular
[K1] can also slow impulse conduction indirectly, by
decreasing IK1 and partially inactivating inward currents.
This happens during ischemia and when K1 accumula-
tion occurs in the intercellular clefts, not immediately
handled by the Na1-K1 pump. This latter mechanism
may contribute to frequency-dependent regulation of
APD and conduction as well (4). IKr is increased by eleva-
tion of extracellular K1 concentration and decreased in
hypokalemia (235, 294, 1115), which is not what would be
expected from its transmembrane concentration gradient
and is explained by hypokalemia-induced acceleration of
rapid IKr inactivation (225). This may have a role in fre-
quency-dependent APD regulation, and it helps in unde-
rstanding why hypokalemia enhances the risk of arrhyth-
mias by causing prolongation of repolarization at slow
heart rate. IKs, unlike IKr, is reduced by elevated [K1]o and
increased by hypokalemia (235, 294). Therefore, IKs may
serve as part of the repolarization reserve in hypokalemic
patients. Hypokalemia and diminished IK1 can decrease
background K1 currents, which may favor ectopic auto-
maticity not counterbalancing existing inward currents
such as If or NCX and may act as enhanced triggers for
arrhythmia development. Hypokalemia was shown to
decrease Na1-K1 pump activity, thereby elevating intra-
cellular [Na1] and leading to increased DAD formation
via enhanced NCX function (1116). Hypokalemia also
decreases IKr and consequently prolongs repolarization
(225, 235, 1117), decreases repolarization reserve, and of-
ten leads to torsade de pointes tachycardia, especially
when K1 channels are already inhibited by concomitant
drug therapy. Hypomagnesemia has a similar effect but
with a different mechanism. The Mg21 ion acts as endo-
gen Ca21 antagonist, and in the case where its serum
level is low it cannot fine-tune the influence of ICa,L in
sinus node function, repolarization, and possible EAD
and DAD formation (1118).
9.3. Proarrhythmic Drug Effects
Not only can diseases, remodeling, serum electrol-
yte disturbances, and genetic disorders contribute to
arrhythmogenesis, but so can drugs, i.e., they may pos-
sess proarrhythmic actions. Positive inotropic drugs like
digitalis, which inhibits the Na1-K1 pump and enhances
Ca21 release of SR, can cause DADs, whereas phospho-
diesterase inhibitors like milrinone or sympathetic s
timulators (1119) like amphetamine, epinephrine, and nor-
epinephrine increase intracellular cAMP levels (1120,
1135
 VARRÓ ET AL.
1121), and they consequently increase If-related and
Ca21 overload-induced automaticity; all of these repre-
sent enhanced triggers for arrhythmias. A large number
of drugs inhibit INa and impulse conduction including
class I antiarrhythmic drugs like quinidine, flecainide,
propafenone, and tricyclic antidepressants (202, 1122,
1123). These drugs, despite the fact that some of them
are used to abolish arrhythmias, can also elicit ventricu-
lar tachyarrhythmia (1124, 1125), presumably by convert-
ing areas in damaged tissue into areas with
unidirectional impulse conduction block, which is one
prerequisite of reentry arrhythmias, i.e., enhancing the
substrate for arrhythmogenesis.
Another proarrhythmic drug effect is prolongation of
ventricular repolarization (1126). This proarrhythmic mech-
anism, which was discussed above, can enhance both
the arrhythmic triggers by inducing EADs and the sub-
strate by enhancing dispersion of repolarization. A con-
stantly growing number of drugs have such effects, such
as class III antiarrhythmics like sotalol and ibutilide, antibi-
otics like erythromycin, antihistamines like terfenadine
and astemizole, antidepressants like sertindole, and anti-
malarial drugs like dihydroartemisinin and piperaquine
(1127). Most of these drugs had been identified to inhibit
IKr or HERG current; therefore, the assessment of HERG
current-blocking properties of drug candidates became
mandatory in cardiac safety testing in drug development
(1128). It must be emphasized that some drugs can induce
repolarization abnormality-related arrhythmias without
apparent repolarization prolongation by impairing repola-
rization reserve (260). Therefore, drug effects on other
repolarizing currents such as IKs, IK1, and Ito should also be
considered to avoid possible proarrhythmic complica-
tions of novel compounds in development. Computer
simulation studies have recently demonstrated the impor-
tance of evaluating multichannel effects for the prediction
of drug-induced arrhythmic risk (715).
For a more detailed overview of proarrhythmic
adverse effects of drugs, we refer the reader to Refs.
108, 597, 1129–1132.
10. CONCLUSIONS
Cardiac arrhythmias such as VF, TdP, and AF still
threaten the lives of millions of patients worldwide.
Although the underlying causes of arrhythmia develop-
ment are variable, including ischemia, heart failure,
HCM, diabetes, extreme endurance training, or genetic
causes, the direct mechanisms leading to these arrhyth-
mias depend on changes of cellular electrophysiological
properties or function of the heart. Therefore, to prevent
or treat cardiac arrhythmias, and their most serious con-
sequences, sudden cardiac death and stroke, improved
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management and prevention of underlying diseases are
needed. This requires a better understanding of the car-
diac electrophysiological function and how it may be
modulated. The latter includes the improved understand-
ing of the nature of cardiac action potentials in various
regions of the heart and the function of the underlying
transmembrane ionic currents, pumps, and the develop-
ment of novel techniques and tools like in silico modeling.
Pathophysiological changes in the expression and func-
tion of transmembrane currents and pumps lead to distur-
bances of impulse formation, conduction, and refract-
oriness of cardiac muscle. These would favor the onset of
“triggers” and providing the “substrate” for these arrhyth-
mias to develop. Therefore, further intensive research is
required to improve our understanding of the physiology,
pathophysiology, and genetic and hormonal modulation
of these ion channels and pumps in order to develop
more efficacious treatment modalities, thereby saving mil-
lions of lives in the future.
CORRESPONDENCE

(varro.andras@med.u-szeged.hu).
A. Varro
ACKNOWLEDGMENTS
We sincerely thank Gabriella Baczko
and Dr. Noe

mi To

th for
administrative work on the manuscript.
GRANTS
This work was supported by the National Research,
Development and Innovation Office [NKFIH-K-119992, and
GINOP-2.3.2-15-2016-00006 (MOLMEDEX) to A.V., NKFIH-K-
128851 to I.B., PD-125402, FK-129117 to N.N.], the János Bolyai
Research Scholarship of the Hungarian Academy of Sciences
to N.N., and the Hungarian Academy of Sciences, as well as a
Wellcome Trust Fellowship in Basic Biomedical Sciences
(214290/Z/18/Z) and an NC3Rs Infrastructure for Impact Award
(NC/P001076/1) to B.R.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by
the authors.
AUTHOR CONTRIBUTIONS
A.V., N.N., L.V., B.R., and I.B. prepared figures; A.V., J.T., N.N.,
E.P., B.R., and I.B. drafted manuscript; A.V., J.T., N.N., L.V., E.P.,
 ION CHANNELS, ACTION POTENTIALS, AND ARRHYTHMIAS
B.R., and I.B. edited and revised manuscript; A.V., J.T., N.N.,
L.V., E.P., B.R., and I.B. approved final version of manuscript;
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